Anxiety Disorders, Fear
Conditions
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
Study design
Eligibility
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
| Measure | Time frame | Description |
|---|---|---|
| Average Correlations Between Average Time Series - Left & Right Hemisphere of the Brain | 10 minutes | 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. |
| Difference in Volume - Left & Right Habenula | 10 minutes | 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. |
| Percent of Correct No Button Presses During Functional MRI | 2000 milliseconds during trial | 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). |
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
| Arm | Count |
|---|---|
| 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 |
| Total | 1,063 |
Baseline characteristics
| Characteristic | Memory Study | Active Avoidance and Sustained Attention Tasks | Valence/Salience Study (ValSal Task) | Motivation Task (Monetary Incentive Delay (MID) Subjects) | Loss Aversion Task | Passive Presentation Study | Resting State Study | Perception Study | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical Healthy Volunteers <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Healthy Volunteers >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Healthy Volunteers Between 18 and 65 years | 97 Participants | 7 Participants | 36 Participants | 187 Participants | 4 Participants | 4 Participants | 190 Participants | 396 Participants | 921 Participants |
| Age, Categorical Patients <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | — | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Patients >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | — | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Patients Between 18 and 65 years | 50 Participants | 0 Participants | 16 Participants | 10 Participants | 9 Participants | — | 53 Participants | 4 Participants | 142 Participants |
| Ethnicity (NIH/OMB) Healthy Volunteers Hispanic or Latino | 5 Participants | 0 Participants | 4 Participants | 15 Participants | 1 Participants | 0 Participants | 21 Participants | 21 Participants | 67 Participants |
| Ethnicity (NIH/OMB) Healthy Volunteers Not Hispanic or Latino | 92 Participants | 7 Participants | 32 Participants | 165 Participants | 3 Participants | 4 Participants | 167 Participants | 367 Participants | 837 Participants |
| Ethnicity (NIH/OMB) Healthy Volunteers Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 7 Participants | 0 Participants | 0 Participants | 2 Participants | 8 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Patients Hispanic or Latino | 4 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 7 Participants | 0 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Patients Not Hispanic or Latino | 44 Participants | 0 Participants | 15 Participants | 9 Participants | 9 Participants | 0 Participants | 44 Participants | 4 Participants | 125 Participants |
| Ethnicity (NIH/OMB) Patients Unknown or Not Reported | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Healthy Volunteers American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Healthy Volunteers Asian | 20 Participants | 0 Participants | 12 Participants | 15 Participants | 1 Participants | 0 Participants | 40 Participants | 47 Participants | 135 Participants |
| Race (NIH/OMB) Healthy Volunteers Black or African American | 26 Participants | 2 Participants | 6 Participants | 42 Participants | 0 Participants | 0 Participants | 47 Participants | 80 Participants | 203 Participants |
| Race (NIH/OMB) Healthy Volunteers More than one race | 2 Participants | 1 Participants | 1 Participants | 4 Participants | 0 Participants | 0 Participants | 8 Participants | 8 Participants | 24 Participants |
| Race (NIH/OMB) Healthy Volunteers Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Healthy Volunteers Unknown or Not Reported | 2 Participants | 0 Participants | 0 Participants | 15 Participants | 1 Participants | 0 Participants | 10 Participants | 19 Participants | 47 Participants |
| Race (NIH/OMB) Healthy Volunteers White | 45 Participants | 4 Participants | 17 Participants | 111 Participants | 2 Participants | 4 Participants | 84 Participants | 242 Participants | 509 Participants |
| Race (NIH/OMB) Patients American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Patients Asian | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants | 0 Participants | 5 Participants | 0 Participants | 12 Participants |
| Race (NIH/OMB) Patients Black or African American | 11 Participants | 0 Participants | 4 Participants | 1 Participants | 1 Participants | 0 Participants | 10 Participants | 2 Participants | 29 Participants |
| Race (NIH/OMB) Patients More than one race | 7 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 0 Participants | 13 Participants |
| Race (NIH/OMB) Patients Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Patients Unknown or Not Reported | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) Patients White | 28 Participants | 0 Participants | 9 Participants | 8 Participants | 4 Participants | 0 Participants | 30 Participants | 2 Participants | 81 Participants |
| Sex: Female, Male Healthy Volunteers Female | 48 Participants | 3 Participants | 21 Participants | 83 Participants | 3 Participants | 1 Participants | 106 Participants | 201 Participants | 466 Participants |
| Sex: Female, Male Healthy Volunteers Male | 49 Participants | 4 Participants | 15 Participants | 104 Participants | 1 Participants | 3 Participants | 84 Participants | 195 Participants | 455 Participants |
| Sex: Female, Male Patients Female | 33 Participants | 0 Participants | 10 Participants | 9 Participants | 9 Participants | 0 Participants | 41 Participants | 2 Participants | 104 Participants |
| Sex: Female, Male Patients Male | 17 Participants | 0 Participants | 6 Participants | 1 Participants | 0 Participants | 0 Participants | 12 Participants | 2 Participants | 38 Participants |
Adverse events
| Event type | EG000 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 / 396 | 0 / 4 | 0 / 165 | 0 / 50 | 0 / 218 | 0 / 57 | 0 / 57 | 0 / 14 | 0 / 22 | 0 / 264 | 0 / 37 | 0 / 118 | 0 / 32 | 0 / 162 | 0 / 58 |
| other Total, other adverse events | 0 / 396 | 0 / 4 | 0 / 165 | 0 / 50 | 0 / 218 | 0 / 57 | 0 / 57 | 0 / 14 | 0 / 22 | 0 / 264 | 0 / 37 | 0 / 118 | 0 / 32 | 0 / 162 | 0 / 58 |
| serious Total, serious adverse events | 0 / 396 | 0 / 4 | 0 / 165 | 0 / 50 | 0 / 218 | 0 / 57 | 0 / 57 | 0 / 14 | 0 / 22 | 0 / 264 | 0 / 37 | 0 / 118 | 0 / 32 | 0 / 162 | 0 / 58 |
Outcome results
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Volunteers | Average Correlations Between Average Time Series - Left & Right Hemisphere of the Brain | Left BNST | 0.9 correlation coefficient (r) | Standard Deviation 0.08 |
| Healthy Volunteers | Average Correlations Between Average Time Series - Left & Right Hemisphere of the Brain | Right BNST | 0.92 correlation coefficient (r) | Standard Deviation 0.07 |
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Volunteers | Difference in Volume - Left & Right Habenula | Right Habenula | 14.9 mm^3 | Standard Deviation 4 |
| Healthy Volunteers | Difference in Volume - Left & Right Habenula | Left Habenula | 18.8 mm^3 | Standard Deviation 6 |
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)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Volunteers | Percent of Correct No Button Presses During Functional MRI | NOGO Trials | 71 Percentage of accurate responses | Standard Deviation 20 |
| Healthy Volunteers | Percent of Correct No Button Presses During Functional MRI | GO Trials | 99 Percentage of accurate responses | Standard Deviation 3 |
| Healthy Volunteers - 7T fMRI | Percent of Correct No Button Presses During Functional MRI | NOGO Trials | 76 Percentage of accurate responses | Standard Deviation 15 |
| Healthy Volunteers - 7T fMRI | Percent of Correct No Button Presses During Functional MRI | GO Trials | 95 Percentage of accurate responses | Standard Deviation 7 |