Brain Imaging Changes in Fear and Anxiety

NCT00047853 | Completed Results FDA Device

• 2 other identifiers: 02032102-M-0321
• Study Type: interventional
• Target: 1,080
• Locations: 1 country
• Sites: 1

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.

Conditions

Anxiety Disorders; Fear

Keywords

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

Outcome Measures

Primary Outcomes (3)

• 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

Study Arms (2)

Healthy Volunteer

EXPERIMENTAL

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: Shock device; Device: Acoustic startle

Patient

EXPERIMENTAL

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

Interventions

Shock device DEVICE

A participant could receive a shock or not receive as shock

Healthy Volunteer; Patient

Acoustic startle DEVICE

Acoustic startle for MEG only

Healthy Volunteer

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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 National Institute of Mental Health (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.
• 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 Diagnostic and Statistical Manual (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 volunteers)
• Speaks English fluently (subjects with Anxiety Disorder)

You may not qualify if:

• Clinically significant organic disease, e.g., cardiovascular disease.
• Clinically significant abnormalities in physical examination.
• Any medical condition that increases risk for fMRI (e.g. pacemaker, metallic foreign body in eye).
• 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 current diagnosis of alcohol or substance abuse ACCORDING TO DSM IV CRITERIA
• Have a lifetime diagnosis of alcohol or substance dependence ACCORDING TO DSM IV CRITERIA.
• 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
• If a healthy volunteer, psychotropic medication within 4 weeks of scanning
• Pregnancy, i.e., a positive Beta-human chorionic gonadotropin (HCG) urine test conducted prior to each experiment session.
• Reynaud's syndrome for the cold pressor test experiment
• Color blindness (for the active avoidance task only)
• 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.

Sponsors & Collaborators

• National Institute of Mental Health (NIMH): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (15)

• 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.

  PMID: 26178381 RESULT

• 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.

  PMID: 27780778 RESULT

• 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.

  PMID: 28392491 RESULT

• 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.

  PMID: 28838469 RESULT

• 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.

  PMID: 29621615 RESULT

• 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.

  PMID: 34448816 DERIVED

• 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.

  PMID: 33150947 DERIVED

• 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.

  PMID: 31256001 DERIVED

• 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.

  PMID: 30289497 DERIVED

• 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.

  PMID: 29382815 DERIVED

• 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.

  PMID: 29213110 DERIVED

• 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.

  PMID: 28842415 DERIVED

• 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.

  PMID: 28555565 DERIVED

• 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.

  PMID: 27369069 DERIVED

• 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.

  PMID: 27110997 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Anxiety Disorders

Interventions

Reflex, Startle

Condition Hierarchy (Ancestors)

Mental Disorders

Intervention Hierarchy (Ancestors)

Reflex; Neurologic Examination; Diagnostic Techniques, Neurological; Diagnostic Techniques and Procedures; Diagnosis; Physical Examination; Nervous System Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Limitations and Caveats

This protocol was a series of sub-studies using sample subjects which explains the number of participants per study.

Results Point of Contact

• Title: Pao, Maryland
• Organization: National Institute of Mental Health

paom@mail.nih.gov

+1 301 435 5770

Study Officials

• Maryland Pao, M.D.

  National Institute of Mental Health (NIMH)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 22, 2002
• First Posted: October 23, 2002
• Study Start: November 4, 2002
• Primary Completion: July 28, 2022
• Study Completion: July 28, 2022
• Last Updated: March 12, 2024
• Results First Posted: March 12, 2024

Record last verified: 2022-08-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)