Multi-level Molecular Profiling of High Acute Stress: a Clinical Study

Multi-level Molecular Profiling of High Acute Stress

Although it is well known that stress plays an important role in the development of neuropsychiatric diseases, the precise role and molecular effects of stress have only been poorly understood. For example, autophagy is essential for energy and cellular homeostasis through protein catabolism, and dysregulation results in compromised proteostasis, stress-coping behavior, and excessive secretion of signaling molecules and inflammatory factors. Therefore, the aim of the project is to analyze the clinical effects of a bungee jump resembling an acute stress event in correlation to autophagy and other underlying, multi-level molecular profiling. Specifically, it is planned to perform multi-level molecular profiling and sleep analysis in a cohort of healthy male individuals before, during, and after a bungee jump compared to a control cohort of healthy males not undergoing a stress event. The resulting findings will advance the role of autophagy during the stress response and hence in the development of psychiatric disorders, and possibly investigate alternative treatment venues on a molecular level, and finally contribute to a better clinical outcome.

Study Overview

• Status: Active, not recruiting
• Conditions: Healthy
• Intervention / Treatment: Behavioral: Bungee jump

Detailed Description

Although it is well known that stress plays an important role in the development of neuropsychiatric diseases, the molecular effects of stress have only been poorly understood. So far it is known that stress leads to an activation of the stress hormone axis followed by an increased release of the stress hormone and glucocorticoid cortisol. Glucocorticoids bind to glucocorticoid receptors that initiate a cellular signal cascade. However, it can be assumed that other factors are involved but a profound understanding of the stress response at the molecular level has not yet been performed yet.

Using a so-called "multi-omics approach" it is possible to determine changes in a large number of molecular groups, such as proteins or lipids to research the underlying mechanisms of diseases. While multi-omics analyzes have already helped gain elementary knowledge in a large number of somatic diseases, the molecular effects of acute stress have not been addressed yet. This will be the primary focus of this study. To achieve this an acute, concise stress reaction closely resembling a genuine stress response is desired. In previous studies, it was shown that bungee jumping triggers such a short, intense stress reaction and the corresponding activation of the stress hormone axis.

To achieve this a cohort of 25-30 healthy male individuals who undergo a bungee jump resembling an acute stress event will be compared to a cohort of 10-20 healthy males who undergo the same experimental design without undertaking a bungee jump or other stress intervention. At different time points (baseline, shortly before and after the intervention, at multiple time points during the intervention as well as around one week follow up after the intervention) serval psychometrical questionnaires will be gathered and blood will be collected. A dexamethasone inhibition test will be performed before the stress intervention. Sleep quality will be additionally assessed during the entire course of the study by actigraphy. On selected days blood will be collected. Following, autophagy activity will be assessed by Western Blot analysis, and mass spectrometry-based proteomics, phosphoproteomics, metabolomics, and lipidomics will be performed. Bioinformatic analysis, statistical evaluation, quality control, and in silico pathway analyses will then specifically identify factors and cascades of relevance.

The aim of the project is to analyze the clinical effects of an acute stress event in correlation to the underlying, multi-level molecular profiling. Longitudinal multi-omic profiling including proteome, metabolome, lipidome, and epigenetic changes will reveal time-series analysis of thousands of molecular changes and an orchestrated composition of autophagy depended signaling. The resulting findings will advance the role of autophagy in the development of psychiatric disorders, and possibly investigate alternative treatment venues on a molecular level, and finally contribute to a better clinical outcome.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Germany
  • Bonn, Germany, 53111
    • University Hospital Bonn, Clinic for psychiatry and psychotherapy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Present written declaration of consent
• Healthy
• Male
• BMI between 18,5 and 24,9 and body weight between 50kg and 120kg

Exclusion Criteria:

• Insufficient linguistic communication
• Drug abuse or alcohol dependency
• regular medication except for L-thyroxine or antihistamines
• known severe eye disease or severely impaired eyesight or hearing
• a known disease of the cardiovascular system, hypertension higher than 160/90mmHg
• known pulmonary disease, e.g. bronchial asthma
• known fractures of the spine or skeletal system of the lower extremity
• surgery within the last 4 to six months
• intervention group: fear of heights

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Interventions group: High stress condition (bungee jump); 25-30 healthy male volunteers participating in a bungee jump	Behavioral: Bungee jump; Bungee jump from a cran
Placebo Comparator: Control group: No stress condition; 10-15 healthy males serving as a control group without undergoing a stress event/intervention	Behavioral: Bungee jump; Bungee jump from a cran

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proteomics and autophagy processes	Change in protein levels of autophagy biomarkers (LC3II & p62) of isolated PBMCs (peripheral blood mononuclear cells) by Western Blotting.	change from baseline to the stress intervention and a 5- 7 day follow up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proteome patterns	Change in protein levels and protein phosphorylation by untargeted mass spectrometry-based proteomics and phosphoproteomics of isolated PBMCs (peripheral blood mononuclear cells).	change from baseline to the stress intervention and a 5- 7 day follow up
Metabolic processes	Metabolic measurements by mass spectrometry, in order to determine variations in plasma metabolites, including targeted analysis of steroid hormones	change from baseline to the stress intervention and a 5- 7 day follow up
Lipid profiling	Targeted and quantitative analysis by mass spectrometry of change in plasma Lipids.	change from baseline to the stress intervention and a 5- 7 day follow up
Saliva Cortisol Levels	Saliva Cortisol Levels in nmol per Liter (nmol/L) after dexamethasone intake will be evaluated and compared ton the control group	comparison between groups
Sleep Efficiency	Assessment of Sleep Efficiency (total time in bed/time asleep during night) by GenActive Actigraphs	change from baseline to the stress intervention and a 5- 7 day follow up
Overall sleep Quality	Sleep diary to assess overall sleep quality assessed as ratio of the total time spent asleep (in hours) to the total amount of time spent in bed (in hours) per night	change from baseline to the stress intervention and a 5- 7 day follow up
Sleep Quality (PSQI)	Pittsburgh Sleep Quality Index (PSQI): self-report questionnaire to assess sleep quality over a 1-month time interval consisting of 19 individual items.	change from baseline to the stress intervention and a 5- 7 day follow up
Mental well-being (WEMWBS)	Warwick-Edinburgh Mental Well-being Scale (WEMWBS): self-reported 14-item scale to assess Overall mental wellbeing, minimum value 14, maximum value 70, high score indicating high well-being	change from baseline to the stress intervention and a5- 7 day follow up
Resilience behavior (Wagnild &Young)	Resilience scale (Wagnild &Young): self-reported 25-item scale to assess overall resilience, minimum value 25, maximum value 175, high score indicating higher resilience	change from baseline to the stress intervention and a 5- 7 day follow up
Phosphoproteome patterns	Change in protein phosphorylation by untargeted mass spectrometry-based phosphoproteomics of isolated PBMCs (peripheral blood mononuclear cells).	change from baseline to the stress intervention and a 5- 7 day follow up
Ubiquitinome patterns	Change in protein ubiquitination levels by untargeted mass spectrometry-based proteomics of isolated PBMCs (peripheral blood mononuclear cells).	change from baseline to the stress intervention and a 5- 7 day follow up

Collaborators and Investigators

• Sponsor: University Hospital, Bonn
• Investigators: Principal Investigator: Nils Gassen, Dr. rer. nat., University Hospital, Bonn

Publications and helpful links

General Publications

• Klein EM, Brahler E, Dreier M, Reinecke L, Muller KW, Schmutzer G, Wolfling K, Beutel ME. The German version of the Perceived Stress Scale - psychometric characteristics in a representative German community sample. BMC Psychiatry. 2016 May 23;16:159. doi: 10.1186/s12888-016-0875-9.
• Ayash S, Schmitt U, Lyons DM, Muller MB. Stress inoculation in mice induces global resilience. Transl Psychiatry. 2020 Jun 19;10(1):200. doi: 10.1038/s41398-020-00889-0.
• Hasin Y, Seldin M, Lusis A. Multi-omics approaches to disease. Genome Biol. 2017 May 5;18(1):83. doi: 10.1186/s13059-017-1215-1.
• Hennig J, Laschefski U, Opper C. Biopsychological changes after bungee jumping: beta-endorphin immunoreactivity as a mediator of euphoria? Neuropsychobiology. 1994;29(1):28-32. doi: 10.1159/000119059.
• de Kloet ER, Joels M, Holsboer F. Stress and the brain: from adaptation to disease. Nat Rev Neurosci. 2005 Jun;6(6):463-75. doi: 10.1038/nrn1683.
• Leistner C, Menke A. How to measure glucocorticoid receptor's sensitivity in patients with stress-related psychiatric disorders. Psychoneuroendocrinology. 2018 May;91:235-260. doi: 10.1016/j.psyneuen.2018.01.023. Epub 2018 Feb 2.
• Lyons DM, Parker KJ, Katz M, Schatzberg AF. Developmental cascades linking stress inoculation, arousal regulation, and resilience. Front Behav Neurosci. 2009 Sep 18;3:32. doi: 10.3389/neuro.08.032.2009. eCollection 2009.
• Nicora G, Vitali F, Dagliati A, Geifman N, Bellazzi R. Integrated Multi-Omics Analyses in Oncology: A Review of Machine Learning Methods and Tools. Front Oncol. 2020 Jun 30;10:1030. doi: 10.3389/fonc.2020.01030. eCollection 2020.
• van Westerloo DJ, Choi G, Lowenberg EC, Truijen J, de Vos AF, Endert E, Meijers JC, Zhou L, Pereira MP, Queiroz KC, Diks SH, Levi M, Peppelenbosch MP, van der Poll T. Acute stress elicited by bungee jumping suppresses human innate immunity. Mol Med. 2011 Mar-Apr;17(3-4):180-8. doi: 10.2119/molmed.2010.00204. Epub 2010 Dec 10.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2021
• Primary Completion (Actual): January 1, 2022
• Study Completion (Anticipated): January 1, 2023

Study Registration Dates

• First Submitted: October 27, 2021
• First Submitted That Met QC Criteria: November 22, 2021
• First Posted (Actual): December 3, 2021

Study Record Updates

• Last Update Posted (Actual): November 10, 2022
• Last Update Submitted That Met QC Criteria: November 9, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Stress; Autophagy; Bungee Jump
• Other Study ID Numbers: HighStress

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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