Biological Response to Brief Psychological Challenge

Overview

The investigators plan to conduct a crossover experimental trial examining physiological responses to a socio-evaluative speech task under laboratory conditions. Participants will attend two laboratory sessions. At one session participants will take part in a brief laboratory stress task and at the other participants will rest for the same period. Measures of cardiovascular response will be assessed at both sessions. In addition, blood will be drawn at multiple time points across a 125 minute period to assess changes in circulating levels of cortisol, catecholamines, markers of inflammation and cell free mitochondrial DNA in response to the task. The investigators expect that the stress task will induce a specific increase in ccf-mtDNA, which will statistically mediate subsequent peak circulating Interleukin-6 and Tumor Necrosis Factor-α levels. In secondary analyses, the investigators will examine whether stress-induced increases in circulating cortisol, epinephrine, and norepinephrine levels correlate with increases in ccf-mtDNA. These studies will establish the kinetics and magnitude of psychological stress-induced ccf-mtDNA release, the association with early stress mediators, and whether ccf-mtDNA mediates the inflammatory response to acute stress in humans.

Full Title of Study: “Transduction of Psychological Stress Into Systematic Inflammation by Mitochondrial DNA Signaling”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Basic Science
    • Masking: Single (Outcomes Assessor)
  • Study Primary Completion Date: March 2024

Detailed Description

The proposed study will examine physiologic responses to acute psychological challenge in the laboratory among healthy adults. It is widely accepted that there is an increase in circulating markers of inflammation following a single bout of laboratory stress. This increase in systemic inflammation is believed to contribute to the damaging health effect of psychological stress. However, to date, the biological mechanisms by which psychological stress is transduced into inflammation are unclear. The investigators' preliminary evidence suggests that mitochondrion may play a role, with stress-induced increases in circulating levels of mitochondria- derived signaling molecules that are known to modulate immune cell function and the production of pro-inflammatory cytokines. To test this possibility, the investigators plan to conduct a crossover experimental trial examining physiological responses to an evaluative speech task under laboratory conditions. The investigators have previously used this task to induce physiological arousal. The investigators plan to recruit 60 non-smoking volunteers (50% female, aged 20-50 years) and test these participants on two occasions separated by at least a month. On one occasion the participants will be exposed to the speech task. On the other occasion, the participants will rest quietly for the same period. Conditions will be counterbalanced. At both visits cardiovascular responses (heart rate, blood pressure, and heart rate variability) will be assessed as measures of autonomic activation before, during and after the task period. Participants will also have an intravenous catheter inserted and blood drawn at ten time points over the two hour testing period on each occasion. Blood samples will be sent to laboratories at the University of Pittsburgh and at Columbia University for the assessment of mitochondria-derived signalling molecules, inflammatory markers, and cortisol levels.

Interventions

  • Behavioral: Socio-evaluative speech task, then Control
    • First session: 5-minute speech task designed to induce physiological arousal in a laboratory setting. Second Sessions: 5-minute rest period.
  • Behavioral: Control, then Socio-evaluative speech task
    • First session: 5-minute rest period. Second session: 5-minute speech task designed to induce physiological arousal in a laboratory setting

Arms, Groups and Cohorts

  • Experimental: Socio-evaluative Speech Stress, then Control
    • Participants will attend two laboratory sessions. At the first session, participants will complete a socio-evaluative speech task, which is a widely used, highly effective way to investigate stress responses in a laboratory setting. Participants will prepare and deliver a brief, 3-minute speech defending themselves against an alleged transgression (e.g., running a stop sign). The speech will be delivered in front of a video camera, a mirror and an audience (the interviewer and another staff member). Participants will be told that their non-verbal behaviors are being evaluated. At the second session, participants will rest quietly for the same period as the speech task, in the absence of the stressor.
  • Experimental: Control, then Socio-Evaluative Speech Stress
    • Participants will attend two laboratory sessions. At the first session, participants will rest quietly for 5 minutes. At the second session, participants will complete a socio-evaluative speech task, which is a widely used, highly effective way to investigate stress responses in a laboratory setting. Participants will prepare and deliver a brief, 3-minute speech defending themselves against an alleged transgression (e.g., running a stop sign). The speech will be delivered in front of a video camera, a mirror and an audience (the interviewer and another staff member). Participants will be told that their non-verbal behaviors are being evaluated.

Clinical Trial Outcome Measures

Primary Measures

  • Change in cell-free mitochondrial DNA
    • Time Frame: 5 minutes before to 5, 10, 20, 30, 45, 60, 75, 90,120 minutes post-task periods
    • Plasma and serum levels of mitochondrial DNA will be assessed as change across all measures using linear mixed models (with subject and day (nested within subject) as random effects, and condition (stress/control) as fixed effects
  • Change in interleukin-6
    • Time Frame: 5 minutes before to 20, 30, 45, 60, 75, 90, 120 post-task periods
    • Plasma levels of interleukin-6 will be assessed as change across all measures using linear mixed models (with subject and day (nested within subject) as random effects, and condition (stress/control) as fixed effects
  • Change in tumor necrosis factor-alpha
    • Time Frame: 5 minutes before to 20, 30, 45, 60, 75, 90, 120 post-task periods
    • Plasma levels of tumor necrosis factor-alpha will be assessed as change across all measures using linear mixed models (with subject and day (nested within subject) as random effects, and condition (stress/control) as fixed effects

Secondary Measures

  • Change in heart rate
    • Time Frame: Continuously assessed from 10 minutes before to 120 minutes after the task periods.
    • Continuous measurement of heart rate will be assessed using a cuff placed on a finger. Linear mixed models (with subject and day (nested within subject) as random effects, and condition (stress/control) as fixed effects will be employed to assess change in heart rate across time.
  • Change in systolic and diastolic blood pressure
    • Time Frame: Continuously assessed from 10 minutes before to 120 minutes after the task periods.
    • Continuous measurement of blood pressure will be assessed using a cuff placed on a finger. Linear mixed models (with subject and day (nested within subject) as random effects, and condition (stress/control) as fixed effects will be employed to assess change in blood pressure across time.
  • Change in cortisol
    • Time Frame: 5 minutes before to 10, 20, 30, 45, 60 minutes post-task periods
    • Circulating levels of cortisol assessed by ELISA will be assessed as change across all measures using linear mixed models (with subject and day (nested within subject) as random effects, and condition (stress/control) as fixed effects
  • Change in epinephrine
    • Time Frame: 5 minutes before to 5, 10, 20, 30, & 60 minutes post-task periods
    • Levels of epinephrine in plasma from blood samples will be assessed as change across all measures using linear mixed models (with subject and day (nested within subject) as random effects, and condition (stress/control) as fixed effects
  • Change in norepinephrine
    • Time Frame: 5 minutes before to 5, 10, 20, 30, & 60 minutes post-task periods
    • Levels of norepinephrine in plasma from blood samples will be assessed as change across all measures using linear mixed models (with subject and day (nested within subject) as random effects, and condition (stress/control) as fixed effects
  • Change in heart rate variability
    • Time Frame: Continuously assessed from 10 minutes before to 120 minutes after the task periods.
    • Interbeat intervals of heart rate assessed by 3-lead EKG will be assessed as change across all measures using linear mixed models (with subject and day (nested within subject) as random effects, and condition (stress/control) as fixed effects
  • Change in Fatigue
    • Time Frame: 2 minutes before and 2 and 120 minutes post-task periods
    • Momentary assessment of fatigue, measured as score on the fatigue subscale on the Profile of Mood States questionnaire in response to the task periods. Scores range from 0 – 20, with higher scores reflecting more fatigue.
  • Change in anger
    • Time Frame: 2 minutes before and 2 and 120 minutes post-task periods
    • Momentary assessment of anger, measured as score on the anger subscale on the Profile of Mood States questionnaire in response to the task periods. Scores range from 0 – 12, with higher scores reflecting more anger.
  • Change in anxious mood
    • Time Frame: 2 minutes before and 2 and 120 minutes post-task periods
    • Momentary assessment of anxious mood, measured as score on the anxiety subscale on the Profile of Mood States questionnaire in response to the task periods. Scores range from 0 – 16, with higher scores reflecting more anxious mood.
  • Change in depressed mood
    • Time Frame: 2 minutes before and 2 and 120 minutes post-task periods
    • Momentary assessment of depressed mood, measured as score on the depression subscale on the Profile of Mood States questionnaire in response to the task periods. Scores range from 0 – 12, with higher scores reflecting more depressed mood.
  • Change in vigor
    • Time Frame: 2 minutes before and 2 and 120 minutes post-task periods
    • Momentary assessment of vigor, measured as score on the vigor subscale on the Profile of Mood States questionnaire in response to the task periods. Scores range from 0 – 12, with higher scores reflecting more vigor.
  • Change in wellbeing
    • Time Frame: 2 minutes before and 2 and 120 minutes post-task periods
    • Momentary assessment of wellbeing, measured as score on the wellbeing subscale on the Profile of Mood States questionnaire in response to the task periods. Scores range from 0 – 12, with higher scores reflecting more wellbeing.
  • Change in calm mood
    • Time Frame: 2 minutes before and 2 and 120 minutes post-task periods
    • Momentary assessment of calm mood, measured as score on the calm subscale on the Profile of Mood States questionnaire in response to the task periods. Scores range from 0 – 16, with higher scores reflecting more calm mood.

Participating in This Clinical Trial

Inclusion Criteria

  • Generally healthy – Non-smokers/illicit drug users – Blood pressure below 140/90 – Weight > 110 lbs – BMI < 30 – Fluent in English – Women — regular menstrual cycles over the past 12 months (defined as 21- 35 days in length) – Able and willing to give informed consent – Willing to abstain from alcohol and vigorous exercise for 24 hours, from food and drinks (other than water) for 3 hours and from non-prescription medications (other than oral contraception) for 2 days before testing. – Willing to attend two laboratory stress testing sessions, give blood though an intravenous catheter, undergo medical evaluation and complete psychosocial questionnaires. Exclusion Criteria:
  • Reported history of chronic systemic immune, metabolic or mitochondrial diseases, or chronic diseases that influence the central nervous, autonomic nervous or neuroendocrine systems, e.g., autoimmune disease, chronic infections, cardiovascular disease, diabetes, chronic kidney or liver disease, cancer treatment. – Reported psychiatric history of schizophrenia or other psychotic illness, or mood disorder. – Resting blood pressure > 140/90 mmHg at baseline testing. – Weight < 110 lbs – BMI equal to or greater than 30 – Report currently taking glucocorticoid, anti-inflammatory, anti-retroviral, immunosuppressant, insulin, antiarrhythmic, antihypertensive, oral hypoglycemic, antidepressant, benzodiazepine or prescription weight loss medications or other medications known to influence the immune, autonomic or neuroendocrine systems. – For women – Post-menopausal or irregular menstrual cycles over the past 12 months. Report current pregnancy or lactation. – Current smokers (defined as having smoked a cigarette in the previous 3 months). – Current illicit drug use (defined as reported use of illicit drugs such as marijuana, cocaine or heroin in the previous 3 months). – Not fluent in English (have used English in everyday speaking and reading for at least 10 years) – Unable or unwilling to give informed consent – Unwilling to abstain from alcohol and vigorous exercise for 24 hours, from food and drinks (other than water) for 3 hours and from non-prescription medications (other than oral contraception) for 2 days prior to testing.
  • Gender Eligibility: All

    Minimum Age: 20 Years

    Maximum Age: 50 Years

    Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

    Investigator Details

    • Lead Sponsor
      • University of Pittsburgh
    • Collaborator
      • National Institute of Mental Health (NIMH)
    • Provider of Information About this Clinical Study
      • Principal Investigator: Anna L. Marsland, Professor – University of Pittsburgh
    • Overall Official(s)
      • Anna L Marsland, Ph.D., Principal Investigator, University of Pittsburgh
    • Overall Contact(s)
      • Anna L Marsland, Ph.D, 4123705622, marsland@pitt.edu

    References

    Trumpff C, Marsland AL, Basualto-Alarcón C, Martin JL, Carroll JE, Sturm G, Vincent AE, Mosharov EV, Gu Z, Kaufman BA, Picard M. Acute psychological stress increases serum circulating cell-free mitochondrial DNA. Psychoneuroendocrinology. 2019 Aug;106:268-276. doi: 10.1016/j.psyneuen.2019.03.026. Epub 2019 Mar 28.

    Trumpff C, Marsland AL, Sloan RP, Kaufman BA, Picard M. Predictors of ccf-mtDNA reactivity to acute psychological stress identified using machine learning classifiers: A proof-of-concept. Psychoneuroendocrinology. 2019 Sep;107:82-92. doi: 10.1016/j.psyneuen.2019.05.001. Epub 2019 May 7.

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