Brain Imaging Changes in Fear and Anxiety

fMRI Investigation of Explicit Cue and Contextual 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.

Study Overview

• Status: Completed
• Conditions: Anxiety Disorders; Fear
• Intervention / Treatment: Device: Acoustic startle; Device: Shock device

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.

• Study Type: Interventional
• Enrollment (Actual): 1080
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

• 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 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, monoamine oxidase (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-human chorionic gonadotropin (HCG) urine test conducted prior to each experiment session.
13. 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.
14. Reynaud's syndrome for the cold pressor test experiment
15. Color blindness (for the active avoidance task only)

ADDITIONAL EXCLUSION CRITERIA FOR PATIENTS:

Patients who would be unable to comply with study procedures or assessments.

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 psychotropic 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Healthy Volunteer; Healthy volunteer will undergo Functional magnetic resonance imaging (fMRI) and/or magneto-encephalography (MEG) and will be scanned during runs of either shock or no shock.	Device: Acoustic startle; Acoustic startle for MEG only; Device: Shock device; A participant could receive a shock or not receive as shock
Experimental: Patient; Participant with a current diagnosis of generalized anxiety disorder (GAD), panic disorder, social anxiety disorder (SAD), specific phobia, posttraumatic stress disorder (PTSD), or major depression will undergo Functional magnetic resonance imaging (fMRI) and will be scanned during runs of either shock or no shock.	Device: Shock device; A participant could receive a shock or not receive as shock

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	10 minutes
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.	10 minutes
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).	2000 milliseconds during trial

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Self-reported measures of anxiety, level of risk, and CS-US contingency awareness.	Self-reported measures of anxiety, level of risk, and CS-US contingency awareness.	End of study visit
Psychophysiological measures	Psychophysiological measures of anxious arousal including the skin conductance response (SCR), heart rate, respiration, and EMG measures of the fear-potentiation of the startle reflex.	End of study visit

Collaborators and Investigators

• Sponsor: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Maryland Pao, M.D., National Institute of Mental Health (NIMH)

Publications and helpful links

General Publications

• Torrisi S, Gorka AX, Gonzalez-Castillo J, O'Connell K, Balderston N, Grillon C, Ernst M. Extended amygdala connectivity changes during sustained shock anticipation. Transl Psychiatry. 2018 Jan 31;8(1):33. doi: 10.1038/s41398-017-0074-6.
• Robinson OJ, Pike AC, Cornwell B, Grillon C. The translational neural circuitry of anxiety. J Neurol Neurosurg Psychiatry. 2019 Dec;90(12):1353-1360. doi: 10.1136/jnnp-2019-321400. Epub 2019 Jun 29.
• Philips RT, Torrisi SJ, Gorka AX, Grillon C, Ernst M. Dynamic Time Warping Identifies Functionally Distinct fMRI Resting State Cortical Networks Specific to VTA and SNc: A Proof of Concept. Cereb Cortex. 2022 Mar 4;32(6):1142-1151. doi: 10.1093/cercor/bhab273.
• Balderston NL, Flook E, Hsiung A, Liu J, Thongarong A, Stahl S, Makhoul W, Sheline Y, Ernst M, Grillon C. Patients with anxiety disorders rely on bilateral dlPFC activation during verbal working memory. Soc Cogn Affect Neurosci. 2020 Dec 24;15(12):1288-1298. doi: 10.1093/scan/nsaa146.
• Gorka AX, Fuchs B, Grillon C, Ernst M. Impact of induced anxiety on neural responses to monetary incentives. Soc Cogn Affect Neurosci. 2018 Nov 8;13(11):1111-1119. doi: 10.1093/scan/nsy082.
• Balderston NL, Liu J, Roberson-Nay R, Ernst M, Grillon C. The relationship between dlPFC activity during unpredictable threat and CO2-induced panic symptoms. Transl Psychiatry. 2017 Nov 30;7(12):1266. doi: 10.1038/s41398-017-0006-5.
• Balderston NL, Hsiung A, Ernst M, Grillon C. Effect of Threat on Right dlPFC Activity during Behavioral Pattern Separation. J Neurosci. 2017 Sep 20;37(38):9160-9171. doi: 10.1523/JNEUROSCI.0717-17.2017. Epub 2017 Aug 21.
• Balderston NL, Hale E, Hsiung A, Torrisi S, Holroyd T, Carver FW, Coppola R, Ernst M, Grillon C. Threat of shock increases excitability and connectivity of the intraparietal sulcus. Elife. 2017 May 30;6:e23608. doi: 10.7554/eLife.23608.
• Torrisi S, Robinson O, O'Connell K, Davis A, Balderston N, Ernst M, Grillon C. The neural basis of improved cognitive performance by threat of shock. Soc Cogn Affect Neurosci. 2016 Nov;11(11):1677-1686. doi: 10.1093/scan/nsw088. Epub 2016 Jun 30.
• Balderston NL, Vytal KE, O'Connell K, Torrisi S, Letkiewicz A, Ernst M, Grillon C. Anxiety Patients Show Reduced Working Memory Related dlPFC Activation During Safety and Threat. Depress Anxiety. 2017 Jan;34(1):25-36. doi: 10.1002/da.22518. Epub 2016 Apr 25.
• Torrisi S, O'Connell K, Davis A, Reynolds R, Balderston N, Fudge JL, Grillon C, Ernst M. Resting state connectivity of the bed nucleus of the stria terminalis at ultra-high field. Hum Brain Mapp. 2015 Oct;36(10):4076-88. doi: 10.1002/hbm.22899. Epub 2015 Jul 14.
• Torrisi S, Nord CL, Balderston NL, Roiser JP, Grillon C, Ernst M. Resting state connectivity of the human habenula at ultra-high field. Neuroimage. 2017 Feb 15;147:872-879. doi: 10.1016/j.neuroimage.2016.10.034. Epub 2016 Oct 22.
• Gorka AX, Torrisi S, Shackman AJ, Grillon C, Ernst M. Intrinsic functional connectivity of the central nucleus of the amygdala and bed nucleus of the stria terminalis. Neuroimage. 2018 Mar;168:392-402. doi: 10.1016/j.neuroimage.2017.03.007. Epub 2017 Apr 6.
• Cornwell BR, Garrido MI, Overstreet C, Pine DS, Grillon C. The Unpredictive Brain Under Threat: A Neurocomputational Account of Anxious Hypervigilance. Biol Psychiatry. 2017 Sep 15;82(6):447-454. doi: 10.1016/j.biopsych.2017.06.031. Epub 2017 Jul 6.
• Torrisi S, Chen G, Glen D, Bandettini PA, Baker CI, Reynolds R, Yen-Ting Liu J, Leshin J, Balderston N, Grillon C, Ernst M. Statistical power comparisons at 3T and 7T with a GO / NOGO task. Neuroimage. 2018 Jul 15;175:100-110. doi: 10.1016/j.neuroimage.2018.03.071. Epub 2018 Apr 3.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): November 4, 2002
• Primary Completion (Actual): July 28, 2022
• Study Completion (Actual): July 28, 2022

Study Registration Dates

• First Submitted: October 22, 2002
• First Submitted That Met QC Criteria: October 22, 2002
• First Posted (Estimated): October 23, 2002

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: February 14, 2024
• Last Verified: August 2, 2022

More Information

Terms related to this study

• Keywords: Anxiety; Stress; Fear; Neuroimaging; Healthy Volunteer (HV); Unpredictability
• Additional Relevant MeSH Terms: Mental Disorders; Anxiety Disorders
• Other Study ID Numbers: 020321; 02-M-0321

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: .We plan to submit de-identified data to the repository.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes