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Brain Imaging Changes in Fear and Anxiety

fMRI Investigation of Explicit Cue and Contextual Fear

Status
Completed
Phases
NA
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00047853
Enrollment
1080
Registered
2002-10-23
Start date
2002-11-04
Completion date
2022-07-28
Last updated
2024-03-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Anxiety Disorders, Fear

Keywords

Stress, Fear, Anxiety, Neuroimaging, Unpredictability, Healthy Volunteer (HV)

Brief summary

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.

Detailed description

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.

Interventions

A participant could receive a shock or not receive as shock

Acoustic startle for MEG only

Sponsors

National Institute of Mental Health (NIMH)
Lead SponsorNIH

Study design

Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE

Eligibility

Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes

Inclusion criteria

* 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 National Institute of Mental Health (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 Diagnostic and Statistical Manual (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

Design outcomes

Primary

MeasureTime frameDescription
Average Correlations Between Average Time Series - Left & Right Hemisphere of the Brain10 minutesThe average bed nucleus of the stria terminalis (BNST) correlations between all averaged time series were extracted from the raters' individual masks. Blood Oxygenation Level Dependent (BOLD) signals were used to extract a mean time series from the BNST masks. This time series was correlated across the rest of the brain using 3dTcorr1D, which computes the correlation coefficient between each voxel time series. Raters were blinded to subject identity for subjective sensory effects at high field and inter-rater and volume measurements for the drawn BNST masks. Correlations were calculated between average time series extracted between all raters' masks for each subject. Two separate analyses for the left and right BNSTs were performed.
Difference in Volume - Left & Right Habenula10 minutesImages were acquired on a 7 T Siemens Magnetom MRI with a 32-channel head coil over 10 minutes. Participants were instructed to keep their eyes open and look at a white fixation cross on a black background during image acquisition. Following manual tracing of the habenula, the volumes of the left and right habenulae for each subject were computed separately. The left and right habenula volumes were then compared using a paired t-test.
Percent of Correct No Button Presses During Functional MRI2000 milliseconds during trialSubjects participated in go/nogo (91% GO trials with the = symbol indicating button push and 9% NOGO trials with the O symbol indicating no push)) task condition during 3 Tesla (3T) or 7 Tesla (7T) functional MRI with periods of threat of shocks and periods of safety when no shock could be administered. During the GNG stimuli were presented on a monitor and randomly distributed. A correct go hit was a response recorded during these 2000 ms to a go trial. Similarly, a correct nogo omission was a no response during the same period to a nogo trial. Performance was first averaged across condition (threat, safe) and trial type (go, nogo) by dividing the number of correct responses by the total number of each trial type. The NOGO and GO behavioral effects were then separately compared between 3T and 7T strength. Accuracy was measured as a percent of correct button presses during fMRI (3T or 7T).

Countries

United States

Participant flow

Recruitment details

15 participants were screen failure and two participants withdrew prior to start of study.

Pre-assignment details

Participants had the option to volunteer for one or more sub-study

Participants by arm

ArmCount
Perception Study
Participants identified the expression on faces or identified the emotion of a word and were asked to respond during these stimuli themselves and during neutral pictures which were paired with these stimuli. Participants could also be asked to judge how long stimuli remained on the screen by making a button press denoting the relative duration of these stimuli compared to durations they learned.
400
Memory Study
Participants performed one or more memory tasks: a) navigated a virtual reality water maze with a joystick to learn the location of an escape platform; b) Behavioral Pattern Separation (BPS) task which consisted of two phases - first participants assign an indoor/outdoor verdict to pictures of neutral objects and completed a memory test. Lastly, participants were asked to remember verbal and nonverbal stimuli which consisted of words, pictures, letters or spatial locations in series of stimuli.
147
Resting State Study
Participants laid still with their eyes open and stared at a fixation cross for 6-9 minutes without falling asleep. During a resting state run, participants did not engage in any task. However, on some rest runs, they were under the threat of a shock or safe from shock.
243
Passive Presentation Study
Participants engaged in simple, passive experience (visual, auditory, tactile) to measure sensory responses under threat and safe conditions. Participants were asked to remain attentive to whether they were at risk of receiving shock or safe from shocks but did not need to respond to the stimuli.
4
Loss Aversion Task
Participants decided between taking or dismissing a series of monetary gambles.
13
Motivation Task (Monetary Incentive Delay (MID) Subjects)
Participants performed one of two versions of the MID task. The first version of the task examined the effect of threat of shock on goal driven/motivational stimuli where subjects made speeded responses to a central target under conditions of potential monetary gain, loss, or neutrality during threat of shock and during safety. During the second version, participants performed the MID task within the MRI scanner.
197
Valence/Salience Study (ValSal Task)
Participants completed the ValSal task involving two motivated behaviors, valence and salience. Valence compared the positive versus negative values tagged to stimuli/situations. Salience examined the subjective importance of stimuli/situations.
52
Active Avoidance and Sustained Attention Tasks
In the active avoidance signal task (AAST), participants performed a modified version of the threat paradigm during which, they held down a button and view sequentially presented pairs of colored squares and were instructed to lift their finger when they see the medium-medium color combination (i.e. go trials), and to refrain from lifting their finger during all other combinations (i.e. stop trials). Participants performed alternating blocks in safe and threat conditions, and each block consisted of a series of go and stop trials. In the sustained attention to response task (SART), subjects participated in go/nogo during periods of threat of shocks and periods of safety, when no shock could be administered.
7
Total1,063

Baseline characteristics

CharacteristicMemory StudyActive Avoidance and Sustained Attention TasksValence/Salience Study (ValSal Task)Motivation Task (Monetary Incentive Delay (MID) Subjects)Loss Aversion TaskPassive Presentation StudyResting State StudyPerception StudyTotal
Age, Categorical
Healthy Volunteers
<=18 years
0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants
Age, Categorical
Healthy Volunteers
>=65 years
0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants
Age, Categorical
Healthy Volunteers
Between 18 and 65 years
97 Participants7 Participants36 Participants187 Participants4 Participants4 Participants190 Participants396 Participants921 Participants
Age, Categorical
Patients
<=18 years
0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants
Age, Categorical
Patients
>=65 years
0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants
Age, Categorical
Patients
Between 18 and 65 years
50 Participants0 Participants16 Participants10 Participants9 Participants53 Participants4 Participants142 Participants
Ethnicity (NIH/OMB)
Healthy Volunteers
Hispanic or Latino
5 Participants0 Participants4 Participants15 Participants1 Participants0 Participants21 Participants21 Participants67 Participants
Ethnicity (NIH/OMB)
Healthy Volunteers
Not Hispanic or Latino
92 Participants7 Participants32 Participants165 Participants3 Participants4 Participants167 Participants367 Participants837 Participants
Ethnicity (NIH/OMB)
Healthy Volunteers
Unknown or Not Reported
0 Participants0 Participants0 Participants7 Participants0 Participants0 Participants2 Participants8 Participants17 Participants
Ethnicity (NIH/OMB)
Patients
Hispanic or Latino
4 Participants0 Participants1 Participants1 Participants0 Participants0 Participants7 Participants0 Participants13 Participants
Ethnicity (NIH/OMB)
Patients
Not Hispanic or Latino
44 Participants0 Participants15 Participants9 Participants9 Participants0 Participants44 Participants4 Participants125 Participants
Ethnicity (NIH/OMB)
Patients
Unknown or Not Reported
2 Participants0 Participants0 Participants0 Participants0 Participants0 Participants2 Participants0 Participants4 Participants
Race (NIH/OMB)
Healthy Volunteers
American Indian or Alaska Native
1 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants1 Participants
Race (NIH/OMB)
Healthy Volunteers
Asian
20 Participants0 Participants12 Participants15 Participants1 Participants0 Participants40 Participants47 Participants135 Participants
Race (NIH/OMB)
Healthy Volunteers
Black or African American
26 Participants2 Participants6 Participants42 Participants0 Participants0 Participants47 Participants80 Participants203 Participants
Race (NIH/OMB)
Healthy Volunteers
More than one race
2 Participants1 Participants1 Participants4 Participants0 Participants0 Participants8 Participants8 Participants24 Participants
Race (NIH/OMB)
Healthy Volunteers
Native Hawaiian or Other Pacific Islander
1 Participants0 Participants0 Participants0 Participants0 Participants0 Participants1 Participants0 Participants2 Participants
Race (NIH/OMB)
Healthy Volunteers
Unknown or Not Reported
2 Participants0 Participants0 Participants15 Participants1 Participants0 Participants10 Participants19 Participants47 Participants
Race (NIH/OMB)
Healthy Volunteers
White
45 Participants4 Participants17 Participants111 Participants2 Participants4 Participants84 Participants242 Participants509 Participants
Race (NIH/OMB)
Patients
American Indian or Alaska Native
0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants1 Participants0 Participants1 Participants
Race (NIH/OMB)
Patients
Asian
2 Participants0 Participants1 Participants1 Participants3 Participants0 Participants5 Participants0 Participants12 Participants
Race (NIH/OMB)
Patients
Black or African American
11 Participants0 Participants4 Participants1 Participants1 Participants0 Participants10 Participants2 Participants29 Participants
Race (NIH/OMB)
Patients
More than one race
7 Participants0 Participants2 Participants0 Participants0 Participants0 Participants4 Participants0 Participants13 Participants
Race (NIH/OMB)
Patients
Native Hawaiian or Other Pacific Islander
0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
Patients
Unknown or Not Reported
2 Participants0 Participants0 Participants0 Participants1 Participants0 Participants3 Participants0 Participants6 Participants
Race (NIH/OMB)
Patients
White
28 Participants0 Participants9 Participants8 Participants4 Participants0 Participants30 Participants2 Participants81 Participants
Sex: Female, Male
Healthy Volunteers
Female
48 Participants3 Participants21 Participants83 Participants3 Participants1 Participants106 Participants201 Participants466 Participants
Sex: Female, Male
Healthy Volunteers
Male
49 Participants4 Participants15 Participants104 Participants1 Participants3 Participants84 Participants195 Participants455 Participants
Sex: Female, Male
Patients
Female
33 Participants0 Participants10 Participants9 Participants9 Participants0 Participants41 Participants2 Participants104 Participants
Sex: Female, Male
Patients
Male
17 Participants0 Participants6 Participants1 Participants0 Participants0 Participants12 Participants2 Participants38 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
EG002
affected / at risk
EG003
affected / at risk
EG004
affected / at risk
EG005
affected / at risk
EG006
affected / at risk
EG007
affected / at risk
EG008
affected / at risk
EG009
affected / at risk
EG010
affected / at risk
EG011
affected / at risk
EG012
affected / at risk
EG013
affected / at risk
EG014
affected / at risk
deaths
Total, all-cause mortality
0 / 3960 / 40 / 1650 / 500 / 2180 / 570 / 570 / 140 / 220 / 2640 / 370 / 1180 / 320 / 1620 / 58
other
Total, other adverse events
0 / 3960 / 40 / 1650 / 500 / 2180 / 570 / 570 / 140 / 220 / 2640 / 370 / 1180 / 320 / 1620 / 58
serious
Total, serious adverse events
0 / 3960 / 40 / 1650 / 500 / 2180 / 570 / 570 / 140 / 220 / 2640 / 370 / 1180 / 320 / 1620 / 58

Outcome results

Primary

Average Correlations Between Average Time Series - Left & Right Hemisphere of the Brain

The average bed nucleus of the stria terminalis (BNST) correlations between all averaged time series were extracted from the raters' individual masks. Blood Oxygenation Level Dependent (BOLD) signals were used to extract a mean time series from the BNST masks. This time series was correlated across the rest of the brain using 3dTcorr1D, which computes the correlation coefficient between each voxel time series. Raters were blinded to subject identity for subjective sensory effects at high field and inter-rater and volume measurements for the drawn BNST masks. Correlations were calculated between average time series extracted between all raters' masks for each subject. Two separate analyses for the left and right BNSTs were performed.

Time frame: 10 minutes

Population: Analysis was done on a sample of healthy participants

ArmMeasureGroupValue (MEAN)Dispersion
Healthy VolunteersAverage Correlations Between Average Time Series - Left & Right Hemisphere of the BrainLeft BNST0.9 correlation coefficient (r)Standard Deviation 0.08
Healthy VolunteersAverage Correlations Between Average Time Series - Left & Right Hemisphere of the BrainRight BNST0.92 correlation coefficient (r)Standard Deviation 0.07
p-value: <0.001ANOVA
Primary

Difference in Volume - Left & Right Habenula

Images were acquired on a 7 T Siemens Magnetom MRI with a 32-channel head coil over 10 minutes. Participants were instructed to keep their eyes open and look at a white fixation cross on a black background during image acquisition. Following manual tracing of the habenula, the volumes of the left and right habenulae for each subject were computed separately. The left and right habenula volumes were then compared using a paired t-test.

Time frame: 10 minutes

Population: Analysis was done on a pilot sample of healthy volunteer participants

ArmMeasureGroupValue (MEAN)Dispersion
Healthy VolunteersDifference in Volume - Left & Right HabenulaRight Habenula14.9 mm^3Standard Deviation 4
Healthy VolunteersDifference in Volume - Left & Right HabenulaLeft Habenula18.8 mm^3Standard Deviation 6
p-value: 0.000093t-test, 2 sided
Primary

Percent of Correct No Button Presses During Functional MRI

Subjects participated in go/nogo (91% GO trials with the = symbol indicating button push and 9% NOGO trials with the O symbol indicating no push)) task condition during 3 Tesla (3T) or 7 Tesla (7T) functional MRI with periods of threat of shocks and periods of safety when no shock could be administered. During the GNG stimuli were presented on a monitor and randomly distributed. A correct go hit was a response recorded during these 2000 ms to a go trial. Similarly, a correct nogo omission was a no response during the same period to a nogo trial. Performance was first averaged across condition (threat, safe) and trial type (go, nogo) by dividing the number of correct responses by the total number of each trial type. The NOGO and GO behavioral effects were then separately compared between 3T and 7T strength. Accuracy was measured as a percent of correct button presses during fMRI (3T or 7T).

Time frame: 2000 milliseconds during trial

Population: Analysis included only participants who completed the Sustained Attention to Response Task (SART)

ArmMeasureGroupValue (MEAN)Dispersion
Healthy VolunteersPercent of Correct No Button Presses During Functional MRINOGO Trials71 Percentage of accurate responsesStandard Deviation 20
Healthy VolunteersPercent of Correct No Button Presses During Functional MRIGO Trials99 Percentage of accurate responsesStandard Deviation 3
Healthy Volunteers - 7T fMRIPercent of Correct No Button Presses During Functional MRINOGO Trials76 Percentage of accurate responsesStandard Deviation 15
Healthy Volunteers - 7T fMRIPercent of Correct No Button Presses During Functional MRIGO Trials95 Percentage of accurate responsesStandard Deviation 7

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026