Study Results
Results available
Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.
View full resultsBasic Information
Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.
Recruitment Status
COMPLETED
Clinical Phase
NA
Total Enrollment
1080 participants
Study Classification
INTERVENTIONAL
Study Start Date
2002-11-04
Study Completion Date
2022-07-28
Brief Summary
Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.
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.
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.
Related Clinical Trials
Explore similar clinical trials based on study characteristics and research focus.
Spatial Context and Fear Learning
NCT02423044
Anxiety Disorders
COMPLETED
Neuroimaging Memories of Fear and Safety in the Human Brain
NCT04975009
Fear Anxiety
PTSD
RECRUITING
NA
Study of Brain Circuitry in Anxiety Disorders
NCT01849432
Posttraumatic Stress Disorder
Panic Disorder
Specific Phobias
COMPLETED
Effects of Duloxetine on Pathological Worry in Patients With Generalized Anxiety Disorder: A fMRI Study
NCT00491348
Worry
Anxiety
TERMINATED
NA
Locating Regions of Interest in Generalized Anxiety Disorder Using Function Magnetic Resonance Imaging (fMRI)
NCT01607710
Generalized Anxiety Disorder
COMPLETED
Detailed Description
Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.
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.
Conditions
See the medical conditions and disease areas that this research is targeting or investigating.
Anxiety Disorders
Fear
Study Design
Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.
Allocation Method
NON_RANDOMIZED
Intervention Model
SINGLE_GROUP
Primary Study Purpose
BASIC_SCIENCE
Blinding Strategy
NONE
Study Groups
Review each arm or cohort in the study, along with the interventions and objectives associated with them.
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.
Group Type
EXPERIMENTAL
Shock device
Intervention Type
DEVICE
A participant could receive a shock or not receive as shock
Acoustic startle
Intervention Type
DEVICE
Acoustic startle for MEG only
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.
Group Type
EXPERIMENTAL
Shock device
Intervention Type
DEVICE
A participant could receive a shock or not receive as shock
Interventions
Learn about the drugs, procedures, or behavioral strategies being tested and how they are applied within this trial.
Shock device
A participant could receive a shock or not receive as shock
Intervention Type
DEVICE
Acoustic startle
Acoustic startle for MEG only
Intervention Type
DEVICE
Eligibility Criteria
Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.
Inclusion Criteria
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)
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
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)
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.
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)
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.
Minimum Eligible Age
18 Years
Maximum Eligible Age
50 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
Yes
Sponsors
Meet the organizations funding or collaborating on the study and learn about their roles.
National Institute of Mental Health (NIMH)
NIH
Sponsor Role
lead
Responsible Party
Identify the individual or organization who holds primary responsibility for the study information submitted to regulators.
Responsibility Role
SPONSOR
Principal Investigators
Learn about the lead researchers overseeing the trial and their institutional affiliations.
Maryland Pao, M.D.
Role: PRINCIPAL_INVESTIGATOR
National Institute of Mental Health (NIMH)
Locations
Explore where the study is taking place and check the recruitment status at each participating site.
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States
Site Status
Countries
Review the countries where the study has at least one active or historical site.
United States
References
Explore related publications, articles, or registry entries linked to this study.
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
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.
Reference Type
DERIVED
Provided Documents
Download supplemental materials such as informed consent forms, study protocols, or participant manuals.
Document Type: Study Protocol and Statistical Analysis Plan
Related Links
Access external resources that provide additional context or updates about the study.
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2002-M-0321.html
NIH Clinical Center Detailed Web Page
Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
02-M-0321
Identifier Type: -
Identifier Source: secondary_id
020321
Identifier Type: -
Identifier Source: org_study_id
More Related Trials
Additional clinical trials that may be relevant based on similarity analysis.
Fmri-based Neurofeedback With Anxious Adolescents Study
NCT02463136
UNKNOWN
PHASE1
Changes in Brain Activity (Functional MRI Study) Before and After Behavioral Therapy of Height Phobia
NCT00302978
COMPLETED
NA
Neurofeedback Enhanced Cognitive Reappraisal Training - Phase 4
NCT06563310
RECRUITING
NA
Investigating Neuronal and Peripheral Markers of Brain Heart Interaction in Healthy Participants Under Stress
NCT05358314
COMPLETED
Effects of Oxytocin on the Functional Architecture of the Brain Before and After Prolonged Naturalistic Fear Induction
NCT05896553
COMPLETED
NA
Neuroplasticity in an Extended Amygdala Network as a Target Mechanism for Attention Bias Modification Outcome
NCT03092609
COMPLETED
NA
Development of Magnetic Resonance Imaging Techniques for Studying Mood and Anxiety Disorders
NCT00397111
RECRUITING
PharmacofMRI (Functional Magnetic Resonance Imaging) of Anxiolytic Medications (Alprazolam)
NCT00703885
COMPLETED
PHASE4
Real-time Neurofeedback Training of Fronto-limbic Regions Functional Connectivity
NCT06033053
RECRUITING
NA
Neurofeedback to Reduce Spontaneous Recovery of Threat Expectancy
NCT07122739
RECRUITING
NA
A Research Study of How Teens With and Without an Anxiety Disorder Make Decisions
NCT00104195
COMPLETED
Electroclinical Correlation of Anxiety
NCT05393518
RECRUITING
NA
Neurofeedback in Clinical High Risk
NCT06492343
NOT_YET_RECRUITING
NA
Neural Activations During Imaginal Exposure in Individuals Fearful of Spiders
NCT03969160
COMPLETED
NA
Modulating Neurocognitive Processes of Learning to Trust and Distrust in Aging
NCT05457725
RECRUITING
NA
FMRI of Stress and Addictive Disorders
NCT01558973
COMPLETED
Childhood Trauma and Escape Decision Dynamics
NCT04290234
UNKNOWN
Compensatory Brain Mechanisms for Amygdala-associated Cognitive Dysfunction: Potential Role of the Cortical Mirror Neuron System
NCT03723733
UNKNOWN
Neurofeedback Enhanced Cognitive Reappraisal Training
NCT06132659
COMPLETED
NA
fMRI Study Examining Effects of D-cycloserine in Specific Phobia
NCT00591825
COMPLETED
PHASE2
Cognitive Process-based Real-time fMRI Neurofeedback in MDD and Rumination
NCT04941066
COMPLETED
NA
Toward a Generalizable Closed-loop Neurofeedback-based BCI for Attention Training
NCT05908253
COMPLETED
NA
Assessing Visual Processing in High Anxiety
NCT04187326
COMPLETED
NA
Neurofeedback Removal of Emotional Information From Mind
NCT06460207
NOT_YET_RECRUITING
NA
Neurocardiac Interactions Evaluated by Anatomic and Physiologic MRI Assessment
NCT02962154
WITHDRAWN