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Stress, Sex, and Fear

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ClinicalTrials.gov Identifier: NCT03786952
Recruitment Status : Recruiting
First Posted : December 25, 2018
Last Update Posted : January 30, 2019
Sponsor:
Collaborator:
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Phillip Zoladz, Ohio Northern University

Brief Summary:
The impact of well-known risk factors for such disorders (stress, biological sex, anxiety-related dispositions) on fear generalization will be examined. Findings from this study may provide insight into how these risk factors influence the development and/or maintenance of psychological disorders that involve overgeneralization of fear and could facilitate future approaches to their treatment.

Condition or disease Intervention/treatment Phase
Psychological Stress Behavioral: Stress immediately before learning in males Behavioral: Sham control immediately before learning in males Behavioral: Stress 30 minutes before learning in males Behavioral: Sham control 30 minutes before learning in males Behavioral: Stress immediately before learning in females Behavioral: Sham control immediately before learning in females Behavioral: Stress 30 minutes before learning in females Behavioral: Sham control 30 minutes before learning in females Not Applicable

Detailed Description:
Many researchers approach the etiology of trauma-, stressor-, and anxiety-related mental disorders from the perspective of classical conditioning processes gone awry. According to this view, abnormal associative relationships between neutral, conditioned stimuli (CSs) and aversive, unconditioned stimuli (USs) underlie pathological anxiety and result in unusually intense fear memories or fear memories that cannot be properly extinguished. Recent work has expanded this view by showing that many psychological disorders involving pathological anxiety are associated with an exaggerated form of the commonly adaptive classical conditioning phenomenon, stimulus generalization, leading individuals with such disorders to respond with fear and anxiety to a variety of environmental contexts and cues that should not be threatening. Few studies have been conducted in humans to better understand the process of fear generalization, and factors that might influence susceptibility to overgeneralize fear have yet to be assessed. It is well-known that stress, biological sex, and anxiety-related dispositions of an individual increase one's susceptibility for pathological anxiety and significantly impact fear learning; thus, it is possible that such factors, alone or in combination, contribute to clinical anxiety by influencing fear generalization processes. Aim 1 of the present study is to determine the effects of acute stress and its physiological correlates on fear generalization in human participants. Because acute stress profoundly impacts cognitive brain areas that underlie generalization, it is predicted that acute stress will enhance or impair fear generalization, depending on when the stressor is administered relative to fear learning. Aim 2 is to assess the role of biological sex in fear generalization and acute stress-induced changes in such processes. Females are more likely than males to develop several psychological disorders that involve pathological anxiety, and research has consistently reported sex-related differences in fear learning and stress-induced alterations of fear learning, effects that have been associated with ovarian hormones. Thus, it is predicted that females will exhibit greater fear generalization than males that will be impacted differently by stress. It is also hypothesized that the observed effects will correlate with estradiol and progesterone in females. The final aim of this project (Aim 3) is to evaluate the relationship between childhood stress, dispositional anxiety, and fear generalization. Early life stress has been repeatedly associated with altered stress responses and the development of anxiety-related phenotypes, yet the influence of childhood stress and trait anxiety on fear generalization have yet tobe examined. This study will be the first to examine how several factors that are known to increase susceptibility for trauma-, stressor, and anxiety-related psychological disorders impact fear generalization in human subjects. The resulting findings will provide important insight into the etiology of such disorders, which could aid future approaches to their treatment.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 600 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Stress, Sex, and the Generalization of Fear
Actual Study Start Date : January 25, 2019
Estimated Primary Completion Date : August 2021
Estimated Study Completion Date : August 2021

Arm Intervention/treatment
Experimental: Stress, immediate, males
Stress immediately before learning in males
Behavioral: Stress immediately before learning in males
Male participants will be exposed to the socially evaluated cold pressor test immediately prior to fear learning. Participants will place their dominant hand in a bath of ice cold water for up to 3 minutes. The participants will also be informed that they are being videotaped for analysis of facial expressions and be asked to stare at a camera throughout the manipulation. Immediately following the acute stressor, participants will undergo the acquisition phase of fear conditioning.

Experimental: Stress, delayed, males
Stress 30 minutes before learning in males
Behavioral: Stress 30 minutes before learning in males
Male participants will be exposed to the socially evaluated cold pressor test 30 minutes prior to fear learning. Participants will place their dominant hand in a bath of ice cold water for up to 3 minutes. The participants will also be informed that they are being videotaped for analysis of facial expressions and be asked to stare at a camera throughout the manipulation. Thirty minutes following the acute stressor, participants will undergo the acquisition phase of fear conditioning.

Sham Comparator: Sham control, immediate, males
Sham control immediately before learning in males
Behavioral: Sham control immediately before learning in males
Male participants will be exposed to the sham control condition (no stress) immediately prior to fear learning. Participants will place their dominant hand in a bath of lukewarm water for up to 3 minutes. Immediately following the sham control condition, participants will undergo the acquisition phase of fear conditioning.

Sham Comparator: Sham control, delayed, males
Sham control 30 minutes before learning in males
Behavioral: Sham control 30 minutes before learning in males
Male participants will be exposed to the sham control condition (no stress) 30 minutes prior to fear learning. Participants will place their dominant hand in a bath of lukewarm water for up to 3 minutes. Thirty minutes following the sham control condition, participants will undergo the acquisition phase of fear conditioning.

Experimental: Stress, immediate, females
Stress immediately before learning in females
Behavioral: Stress immediately before learning in females
Female participants will be exposed to the socially evaluated cold pressor test immediately prior to fear learning. Participants will place their dominant hand in a bath of ice cold water for up to 3 minutes. The participants will also be informed that they are being videotaped for analysis of facial expressions and be asked to stare at a camera throughout the manipulation. Immediately following the acute stressor, participants will undergo the acquisition phase of fear conditioning.

Experimental: Stress, delayed, females
Stress 30 minutes before learning in females
Behavioral: Stress 30 minutes before learning in females
Female participants will be exposed to the socially evaluated cold pressor test 30 minutes prior to fear learning. Participants will place their dominant hand in a bath of ice cold water for up to 3 minutes. The participants will also be informed that they are being videotaped for analysis of facial expressions and be asked to stare at a camera throughout the manipulation. Thirty minutes following the acute stressor, participants will undergo the acquisition phase of fear conditioning.

Sham Comparator: Sham control, immediate, females
Sham control immediately before learning in females
Behavioral: Sham control immediately before learning in females
Female participants will be exposed to the sham control condition (no stress) immediately prior to fear learning. Participants will place their dominant hand in a bath of lukewarm water for up to 3 minutes. Immediately following the sham control condition, participants will undergo the acquisition phase of fear conditioning.

Sham Comparator: Sham control, delayed, females
Sham control 30 minutes before learning in females
Behavioral: Sham control 30 minutes before learning in females
Female participants will be exposed to the sham control condition (no stress) 30 minutes prior to fear learning. Participants will place their dominant hand in a bath of lukewarm water for up to 3 minutes. Thirty minutes following the sham control condition, participants will undergo the acquisition phase of fear conditioning.




Primary Outcome Measures :
  1. EMG responses to CS+ during acquisition [ Time Frame: Fear acquisition on Day 1 ]
    Eyeblink startle responses following presentation of the CS+ during acquisition (i.e., fear learning) on Day 1. The eyeblink component of the acoustic startle response will be measured by EMG recordings (microvolts) of the right orbicularis oculi muscle. Recording electrodes will be placed 1 cm below the pupil and the lateral canthus, and a ground electrode will be placed behind the right ear over the mastoid. EMG startle responses will be defined as the maximum amplitude of eyeblink muscle contraction 20-200 ms after the startle probe, which will be presented 5210 ms following CS+ onset. All EMG data will be acquired via the EMG module of the Biopac MP150 system.

  2. EMG responses to CS+ and generalization stimuli during generalization testing [ Time Frame: Generalization testing on Day 2 ]
    Eyeblink startle responses following presentation of the CS+ and generalization stimuli during generalization testing on Day 2. The eyeblink component of the acoustic startle response will be measured by EMG recordings (microvolts) of the right orbicularis oculi muscle. Recording electrodes will be placed 1 cm below the pupil and the lateral canthus, and a ground electrode will be placed behind the right ear over the mastoid. EMG startle responses will be defined as the maximum amplitude of eyeblink muscle contraction 20-200 ms after the startle probe, which will be presented 5210 ms following CS+ or generalization stimuli onset. All EMG data will be acquired via the EMG module of the Biopac MP150 system.

  3. EDA responses to CS+ during acquisition [ Time Frame: Fear acquisition on Day 1 ]
    Electrodermal activity responses following presentation of the CS+ during acquisition (i.e., fear learning) on Day 1. EDA (i.e., skin conductance; microsiemens) will be recorded by placing electrodes on the hypothenar surface of the non-dominant hand to quantify participants' autonomic responses. EDA responses will be quantified by calculating the average increase (from a 1 s pre-stimulus baseline) 3-6 s after CS+ onset. All EDA data will be acquired via the EDA module of the Biopac MP150 system.

  4. EDA responses to CS+ and generalization stimuli during generalization testing [ Time Frame: Generalization testing on Day 2 ]
    Electrodermal activity responses following presentation of the CS+ and generalization stimuli during generalization testing on Day 2. EDA (i.e., skin conductance; microsiemens) will be recorded by placing electrodes on the hypothenar surface of the non-dominant hand to quantify participants' autonomic responses. EDA responses will be quantified by calculating the average increase (from a 1 s pre-stimulus baseline) 3-6 s after CS+ or generalization stimuli onset. All EDA data will be acquired via the EDA module of the Biopac MP150 system.

  5. US expectancy ratings to CS+ during acquisition [ Time Frame: Fear acquisition on Day 1 ]
    A three-button response keypad (Superlab, Cedrus Corporation) will be used during acquisition on Day 1 to record participants' expectancy of the US following the CS+. Participants will be instructed to press, within 3 seconds of stimulus onset, a button marked "+" if they expect the tone to be followed by the US, a button marked "-" if they do not expect the tone to be followed by the US, or a button marked "0" if they are uncertain. For the purpose of data analysis, + will be scored +1, - will be scored -1, and 0 will be scored 0.

  6. US expectancy ratings to CS+ and generalization stimuli during generalization testing [ Time Frame: Generalization testing on Day 2 ]
    A three-button response keypad (Superlab, Cedrus Corporation) will be used during generalization testing on Day 2 to record participants' expectancy of the US following the CS+ and generalization stimuli. Participants will be instructed to press, within 3 seconds of stimulus onset, a button marked "+" if they expect the tone to be followed by the US, a button marked "-" if they do not expect the tone to be followed by the US, or a button marked "0" if they are uncertain. For the purpose of data analysis, + will be scored +1, - will be scored -1, and 0 will be scored 0.


Secondary Outcome Measures :
  1. Change in baseline salivary cortisol (nmol/l) [ Time Frame: Day 1 (change from baseline to 25 min post-stress) ]
    Saliva samples will be collected from participants prior to undergoing the stress or sham control condition (baseline) and then 25 min later. The change in salivary cortisol levels will be analyzed. Salivary cortisol (nmol/l) will be measured by enzyme immunoassays (Salimetrics LLC).

  2. Change in baseline salivary alpha-amylase (U/ml) [ Time Frame: Day 1 (change from baseline to immediately after stress) ]
    Saliva samples will be collected from participants prior to undergoing the stress or sham control condition (baseline) and then immediately after the manipulation. The change in salivary alpha-amylase levels will be analyzed. Salivary alpha-amylase (U/ml) will be measured by enzyme immunoassay (Salimetrics LLC).

  3. Average subjective pain, as assessed by verbal self report [ Time Frame: Stress or sham control condition on Day 1 ]
    During the stress or sham control manipulation, participants will rate the painfulness of the water bath at 1-minute intervals on an 11-point scale ranging from 0-10, with 0 = lack of pain and 10 = unbearable pain. The obtained ratings will be averaged and analyzed.

  4. Average subjective stress, as assessed by verbal self report [ Time Frame: Stress or sham control condition on Day 1 ]
    During the stress or sham control manipulation, participants will rate the stressfulness of the water bath at 1-minute intervals on an 11-point scale ranging from 0-10, with 0 = lack of stress and 10 = unbearable stress. The obtained ratings will be averaged and analyzed.

  5. Change in heart rate (bpm) [ Time Frame: Day 1 (change from baseline to during stress or sham control manipulation) ]
    Heart rate (bpm) measurements will be taken via the PPG module of the Biopac MP150 system from participants prior to undergoing the stress or sham control condition (baseline) and then halfway through the manipulation.The change in heart rate will be analyzed.

  6. Change in salivary progesterone (pg/ml) [ Time Frame: Day 1 (change from baseline to 25 min post-stress) ]
    Saliva samples will be collected from participants prior to undergoing the stress or sham control condition (baseline) and then 25 min later. The change in salivary progesterone levels will be analyzed. Salivary progesterone (pg/ml) will be measured by enzyme immunoassays (Salimetrics LLC).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • 18 years of age
  • Registered student at Ohio Northern University in Ada, Ohio

Exclusion Criteria:

  • Regular use of tobacco or recreational drugs (e.g., marijuana, cocaine, heroin, etc.)
  • Previous diagnosis of Raynaud's disease or peripheral vascular disease
  • Previous diagnosis of skin diseases (e.g., severe psoriasis, eczema, scleroderma)
  • History of syncope or vasovagal response to stress
  • History of any heart conditions or cardiovascular issues (e.g., high blood pressure)
  • History of severe head trauma
  • Current treatment with narcotics, beta-blockers, steroids, or contraceptives
  • Previous diagnosis of substance use disorder
  • Regular nightshift work
  • Hearing loss
  • Consumed alcohol in past 24 hours
  • Engaged in strenuous exercise in past 24 hours
  • Ate or drank anything but water in past 2 hours

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03786952


Contacts
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Contact: Phillip Zoladz, Ph.D. 419-772-2142 p-zoladz@onu.edu

Locations
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United States, Ohio
Ohio Northern University Recruiting
Ada, Ohio, United States, 45810
Contact: Phillip Zoladz, Ph.D.    419-772-2142    p-zoladz@onu.edu   
Principal Investigator: Phillip Zoladz, Ph.D.         
Sponsors and Collaborators
Ohio Northern University
National Institute of Mental Health (NIMH)
Investigators
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Principal Investigator: Phillip Zoladz, Ph.D. Ohio Northern University

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Responsible Party: Phillip Zoladz, Associate Professor, Ohio Northern University
ClinicalTrials.gov Identifier: NCT03786952     History of Changes
Other Study ID Numbers: 1R15MH116337-01A1 ( U.S. NIH Grant/Contract )
R15MH116337 ( U.S. NIH Grant/Contract )
First Posted: December 25, 2018    Key Record Dates
Last Update Posted: January 30, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Phillip Zoladz, Ohio Northern University:
stress
sex
fear
generalization
cortisol
alpha-amylase
estradiol
progesterone

Additional relevant MeSH terms:
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Stress, Psychological
Behavioral Symptoms