Effects of Arousal and Stress in Anxiety

Effects of Arousal and Stress on Classical Conditioning

This study has several parts. One part will examine the influence of factors such as personality and past experience on reactions to unpleasant stimuli. Others will examine the effect of personality and emotional and attentional states on learning and memory.

When confronted with fearful or unpleasant events, people can develop fear of specific cues that were associated with these events as well as to the environmental context in which the events occurred via a process called classical conditioning. Classical conditioning has been used to model anxiety disorders, but the relationship between stress and anxiety and conditioned responses remains unclear. This study will examine the relationship between cued conditioning and context conditioning . This study will also explore the acquisition and retention of different types of motor, emotional, and cognitive associative processes during various tasks that range from mildly arousing to stressful.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Device: Shock Device; Device: Auditory Startle Device

Detailed Description

Objective: Fear and anxiety are adaptive responses to different types of threats. Fear is a short-duration response evoked by explicit threat cues and anxiety a more sustained state of apprehension evoked by unpredictable threat. This protocol studied fear using Pavlovian fear conditioning in two studies. Studies 1 and 3. Study 2 focused on anxiety. Studies 1 and 3 will be discontinued to focus uniquely on the study of anxiety. Specifically, we will examine the interactions between anxiety induced experimentally using verbal threat and cognitive processes. We will seek to 1) characterize the effect of anxiety on key cognitive processes including working memory and attention control and 2) examine the extent to which performance of cognitive tasks distract from anxiety.

Study population: This more-than-minimal-risk protocol will test medically and psychiatrically healthy volunteers aged 18-50. Pregnant or nursing women will be excluded.

Method: Fear and anxiety will be measured using the startle reflex to brief and loud sounds. Fear conditioning will be assessed using shock as unconditioned stimulus. Cognitive performance will be examined during periods of unpredictable shock anticipation.

Outcome measures: The study will include cognitive performance and measure of aversive states, primarily the startle reflex.

• Study Type: Interventional
• Enrollment (Actual): 1418
• 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:
• Males and females
• Age 18-50

EXCLUSION CRITERIA:

• Pregnancy
• Any current ongoing medical illness
• Current Axis I disorders
• Past significant psychiatric disorders (e.g., psychotic disorders) according to Diagnostic and Statistical Manual (DSM)-IV
• Current alcohol or substance abuse according to DSM-IV criteria
• History of alcohol or substance dependence based on DSM-IV criteria within 6 months prior to screening
• Current psychotropic medication use
• Current or past organic central nervous system disorders, including but not limited to seizure disorder or neurological symptoms of the wrist and arms (e.g., carpal tunnel syndrome). The latter exclusion is for shock studies only.
• Positive urine toxicology screen
• Employees of National Institute of Mental Health (NIMH) or an immediate family member of a NIMH employee.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Healthy volunteers; Sub-study A: Working memory task / Participant performed a working memory task in two conditions, under threat of shock and in safety and asked to remember verbal and nonverbal stimuli from the current stimulus on the screen (N-back task) Sub-study C: Sustained attention to response task (SART) / participant was presented with stimuli and either initiated a response (i.e. "go") or inhibited their response (i.e. "stop") based on what stimuli were presented Sub-study D: Stroop task/ In the classic Stroop test, the name of a color is printed in a color that conflicts or does not conflict with the word. In the emotional Stroop, the words emotional words. The participant's task was to name the color of the word Pilot studies / (1) Shocks were delivered via electrodes located on the forearm or fingers while participant performed a working memory or vigilance task or (2) Subject performed cognitive tasks during alternating safe and threat periods

Device: Shock Device; Shock Device; Device: Auditory Startle Device; Auditory Startle Device

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Go Correct Hits Followed by Button Press	Subjects participated in go/no go (GNG) task condition during periods of threat of shocks and periods of safety when no shock could be administered. During the GNG stimuli were presented on a monitor. In the GNG task, participants were asked to respond to frequent 'go' stimuli ('=') by pressing the '2' on the keypad of a computer keyboard and to withhold their response to infrequent 'nogo' stimuli ('O'). Stimuli were randomly distributed. A correct go hit was a response recorded during these 2000 millisecond (ms) to a go trial. Similarly, a correct nogo omission was a no response during the same period to a nogo trial. Performance was determined for each condition (threat, safe) and trial type (go, nogo) by dividing the number of correct response by the total number of each trial type.	250 ms at a rate of one every 2000 ms
Nogo Trials Followed by no Button Press	Subjects participated in go/no go (GNG) task condition during periods of threat of shocks and periods of safety when no shock could be administered. During the GNG stimuli were presented on a monitor. In the GNG task, participants were asked to respond to frequent 'go' stimuli ('=') by pressing the '2' on the keypad of a computer keyboard and to withhold their response to infrequent 'nogo' stimuli ('O'). Stimuli were randomly distributed. A correct go hit was a response recorded during these 2000 millisecond (ms) to a go trial. Similarly, a correct nogo omission was a no response during the same period to a nogo trial. Performance was determined for each condition (threat, safe) and trial type (go, nogo) by dividing the number of correct response by the total number of each trial type.	250 ms at a rate of one every 2000 ms
Correct-go Reaction Time (RT)	Correct go responses were go trials followed by button press. Mean reaction time (RT) was calculated for correct-go to evaluate speed-accuracy trade-off.	2000 ms during trial
Response to Startle Reflex	The startle reflex was elicited with a 103-decibel (dB) white noise (40-ms duration) delivered via headphone. The eyeblink component of the startle reflex was recorded binaurally with two AgCl electrodes placed under the left eye. The peak startle/eyeblink reflex magnitude was determined in the 20-100 ms timeframe. The shock was administered either on the left wrist or on the left middle and ring fingers, depending on where the desired intensity was reached. Startle stimuli were delivered between two go trials and go trials that followed a startle stimulus were not included in the analysis. A shock was delivered in two of the four threat blocks in each sequence, just prior to the last go trial, which was not included in the analysis (for a total of 4 shocks). Shock could be administered only in the threat condition and never in the safe condition. The results were analyzed using a Condition (safe, threat) x Task (task, no task) repeated ANOVA.	20-100 ms window following the onset of the startle stimulus
Subjective Measures of Level of Anxiety	Subjects retrospectively rated their level of anxiety using a scale of 1-10 where 1 = "not at all anxious" and 10 = "extremely anxious" at the end of each block of a sequence for a total of eight blocks. A block was defined as a combination of a condition (safe or threat) and a task (task or no task). The results were analyzed using a Condition (safe, threat) x Task (task, no task) repeated ANOVA.	Every 100 sec repeated 8 times

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measure of Attention Control	Subjects completed the Attention Control Scale (ACS) prior to start of the study. The ACS is a 20-item self-report scale that measures attentional focusing (9 items) and attentional shifting (11 items) rated on a four-point likert scale from "1 - almost never" to "4 - always" with total score range of 20 to 80. Higher score on ACS reflect better ability to direct and maintain attention.	1-3 weeks before start of study
Measure of Level of Anxiety	The level of anxiety was assessed using the Trait Anxiety Inventory questionnaire. The Trait Anxiety Scale (T-Anxiety) evaluates relatively stable aspects of "anxiety proneness", including general states of calmness, confidence, and security. The Trait Anxiety Scale has 20 items. All items are rated on a 4-point scale: 1 = almost never, 2 = sometimes, 3 = often, and 4 = almost always.. The scale has a minimum score of 20 and a maximum score of 80. Higher score indicates greater anxiety. Trait Anxiety score was measured prior to start of the study.	1-3 weeks before start of study

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

• Grillon C, Ameli R, Goddard A, Woods SW, Davis M. Baseline and fear-potentiated startle in panic disorder patients. Biol Psychiatry. 1994 Apr 1;35(7):431-9. doi: 10.1016/0006-3223(94)90040-x.
• Grillon C, Morgan CA 3rd. Fear-potentiated startle conditioning to explicit and contextual cues in Gulf War veterans with posttraumatic stress disorder. J Abnorm Psychol. 1999 Feb;108(1):134-42. doi: 10.1037//0021-843x.108.1.134.
• Phillips RG, LeDoux JE. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci. 1992 Apr;106(2):274-85. doi: 10.1037//0735-7044.106.2.274.
• Grillon C, Ernst M. A way forward for anxiolytic drug development: Testing candidate anxiolytics with anxiety-potentiated startle in healthy humans. Neurosci Biobehav Rev. 2020 Dec;119:348-354. doi: 10.1016/j.neubiorev.2020.09.024. Epub 2020 Oct 7.
• Grillon C, Lago T, Stahl S, Beale A, Balderston N, Ernst M. Better cognitive efficiency is associated with increased experimental anxiety. Psychophysiology. 2020 Aug;57(8):e13559. doi: 10.1111/psyp.13559. Epub 2020 Mar 17.
• Sarigiannidis I, Grillon C, Ernst M, Roiser JP, Robinson OJ. Anxiety makes time pass quicker while fear has no effect. Cognition. 2020 Apr;197:104116. doi: 10.1016/j.cognition.2019.104116. Epub 2019 Dec 26.
• 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.
• Balderston NL, Hsiung A, Liu J, Ernst M, Grillon C. Reducing State Anxiety Using Working Memory Maintenance. J Vis Exp. 2017 Jul 19;(125):55727. doi: 10.3791/55727.
• Lago T, Davis A, Grillon C, Ernst M. Striatum on the anxiety map: Small detours into adolescence. Brain Res. 2017 Jan 1;1654(Pt B):177-184. doi: 10.1016/j.brainres.2016.06.006. Epub 2016 Jun 6.
• 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.
• Grillon C, Robinson OJ, Krimsky M, O'Connell K, Alvarez G, Ernst M. Anxiety-mediated facilitation of behavioral inhibition: Threat processing and defensive reactivity during a go/no-go task. Emotion. 2017 Mar;17(2):259-266. doi: 10.1037/emo0000214. Epub 2016 Sep 19.
• Grillon C, Robinson OJ, Mathur A, Ernst M. Effect of attention control on sustained attention during induced anxiety. Cogn Emot. 2016;30(4):700-12. doi: 10.1080/02699931.2015.1024614. Epub 2015 Apr 22.
• Lago TR, Hsiung A, Leitner BP, Duckworth CJ, Balderston NL, Chen KY, Grillon C, Ernst M. Exercise modulates the interaction between cognition and anxiety in humans. Cogn Emot. 2019 Jun;33(4):863-870. doi: 10.1080/02699931.2018.1500445. Epub 2018 Jul 23.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2001
• Primary Completion (Actual): July 28, 2022
• Study Completion (Actual): July 28, 2022

Study Registration Dates

• First Submitted: November 10, 2001
• First Submitted That Met QC Criteria: November 10, 2001
• First Posted (Estimated): November 12, 2001

Study Record Updates

• Last Update Posted (Actual): January 9, 2024
• Last Update Submitted That Met QC Criteria: January 5, 2024
• Last Verified: July 28, 2022

More Information

Terms related to this study

• Keywords: Stress; Healthy Volunteer; Learning; Normal Control; Fear Conditioning; Normal Volunteers; Classical Conditioning
• Other Study ID Numbers: 010185; 01-M-0185

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: We will provide de-identified data to repositories but no identifiable data.

Drug and device information, study documents

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