Mitochondrial Stress, Brain Imaging, and Epigenetics (MiSBIE)

The Mitochondrial Stress, Brain Imaging, and Epigenetics Study

The MiSBIE study collects biological, behavioral, psychosocial, neuropsychological, and brain imaging data in participants with either: normal mitochondrial function, individuals with the m.3243A>G mitochondrial DNA (mtDNA) mutation, and individuals a single large-scale mtDNA deletion. These defects induce mitochondrial allostatic load (MAL). The 2-day protocol, plus home-based data collection, will provide a comprehensive assessment of the multi-systemic dysregulation associated with MAL or mitochondrial dysfunction, and the link to physical and mental health-related symptoms.

Aim 1: Determine the influence of MAL on systemic AL biomarkers.

Aim 2: Establish the influence of MAL on stress reactivity profiles.

Aim 3. Examine the association between MAL and psychological functioning.

Study Overview

• Status: Completed
• Conditions: Mitochondrial Diseases
• Intervention / Treatment: Behavioral: Trier social stress test

Detailed Description

Age-related physical and cognitive decline, as well as the risk of neurological diseases, are increased by the effects of psychosocial stress. Psychosocial stress triggers neuroendocrine, metabolic, cardiovascular, and inflammatory changes in the body. These changes vary in nature and magnitude between individuals, and are associated with long-term disease risk. However, the biological determinants of the stress response are not well understood.

This project aims to translate the preclinical findings (how mitochondria regulate the different organ systems and major stress response axes are activated during psychological stress) by studying a population of individuals with varying degree of mitochondrial dysfunction, and to test potential neural mechanism, and why some individuals respond more strongly than others to the same stressor.

Each participant will be studied over two consecutive days. Participants will be housed on campus to standardize study conditions. On Day 1, participants will donate blood and saliva, undergo a neuropsychological assessment, and complete questionnaires to assess psychosocial functioning and psychiatric symptoms. After lunch, the investigator will monitor dynamic changes in mental health-related biological outcomes (positive and negative affect, circulating levels of the inflammatory cytokine IL-6, and salivary cortisol) in response to a standardized laboratory challenge. On Day 2, participants will undergo a medical evaluation to assess clinical symptoms and undergo a whole brain neuroimaging session where both resting and stress elicited activity will be measured. A variant of the same stressor as on Day 1 will be used in the neuroimaging session. Participants will then be debriefed, concluding the individuals participation in the study. Participants also complete a home-based saliva and stool collection to examine diurnal variation in salivary hormones, and to examine microbiome composition. This translational project will generate a unique combination of complimentary molecular, cellular, and neuroimaging data that will advance our understanding of the links between mitochondria, the brain, and mental health-related outcomes.

• Study Type: Interventional
• Enrollment (Actual): 110
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Irving Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Men and women patients between 18 and 55 years of age
• Willing to provide saliva samples and have venous catheter installed for blood collection during the hospital visit
• Willing to provide informed consent and capacity to consent
• Use of effective method of birth control for women of childbearing capacity
• English Speaking

Exclusion Criteria:

• Individuals with cognitive deficit incapable of providing informed consent will not be included
• Symptoms of flu or other seasonal infection four weeks preceding hospital visit
• Raynaud's syndrome (Raynaud phenomenon)
• Involvement in any therapeutic trials listed on clinicaltrials.gov, including exercise
• Metal inside or outside the body or claustrophobia prohibitive to MRI testing
• Diagnosed with mitochondrial disease m.3243A>G, or large scale mtDNA deletion (for healthy controls)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Healthy controls; No diagnosis of mitochondrial disease	Behavioral: Trier social stress test; The Trier social stress test (TSST) is a tool for investigating psychobiological stress responses in a laboratory setting. It is a laboratory procedure used to reliably induce stress in human research participants. The study is not examining or validating the test itself but rather using it as a tool to measure the response/focus of study.; Other Names: TSST
Experimental: Mutation; Participants carrying the m.3243A>G point mutation, without a diagnosis of MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes)	Behavioral: Trier social stress test; The Trier social stress test (TSST) is a tool for investigating psychobiological stress responses in a laboratory setting. It is a laboratory procedure used to reliably induce stress in human research participants. The study is not examining or validating the test itself but rather using it as a tool to measure the response/focus of study.; Other Names: TSST
Experimental: Mutation with MELAS; Participants carrying the m.3243A>G point mutation, with a diagnosis of MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes)	Behavioral: Trier social stress test; The Trier social stress test (TSST) is a tool for investigating psychobiological stress responses in a laboratory setting. It is a laboratory procedure used to reliably induce stress in human research participants. The study is not examining or validating the test itself but rather using it as a tool to measure the response/focus of study.; Other Names: TSST
Experimental: Deletion; Participants carrying a single, large-scale mtDNA deletion	Behavioral: Trier social stress test; The Trier social stress test (TSST) is a tool for investigating psychobiological stress responses in a laboratory setting. It is a laboratory procedure used to reliably induce stress in human research participants. The study is not examining or validating the test itself but rather using it as a tool to measure the response/focus of study.; Other Names: TSST

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average TSST-induced Elevation in Cortisol	This is designed to measure cortisol reactivity to the trier social stress test (TSST), quantified from salivary cortisol (LC-MS) over an 8-timepoints timecourse. The elevation will be measured as the area under the curve (AUC) for the cortisol time course.	Day 1 post challenge (approximately 2 hours)
Average Allostatic Load Index	Groups will be compared on a quantitative allostatic load (AL) index integrating baseline fasting measures of neuroendocrine, immune and metabolic systems, urinary catecholamines, hematological measures, and hair/diurnal cortisol levels. 32 different biomarkers were analyzed for this outcome. The full range of the allostatic load index score is 0 to 32. A lower score is considered better, and a higher score is considered worse.	Blood collected on Day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average TSST-induced Elevation in Heart Rate	Groups will be compared on heart rate (HR) as a measure of cardiovascular reactivity to stress, monitored using a continuous 3-lead ECG. The elevation will be computed from the baseline HR to the peak HR reached during the TSST.	Baseline and 2 hours post challenge on Day 1
Correlation Between Anxiety and Mitochondrial Respiration	The association between mitochondrial respiration using extracellular flux analysis (Seahorse) on blood lymphocytes, and anxiety symptoms measured using the state and trait anxiety inventory (STAI), will be quantified by a linear regression across all study participants.	Day 1
Average Neuropsychological Function	The fluency/initiation domain of executive functioning was assessed using the Delis-Kaplan Executive Function System (D-KEFS) Verbal Fluency Test, specifically Condition 1: Letter Fluency total correct. Raw scores were converted to Z-scores based on the control group. A Z-score of 0 represents the mean of the control group, with positive values indicating better performance and negative values indicating worse performance.	Day 2 neuropsychological session

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: National Institute of Mental Health (NIMH); Massachusetts General Hospital; Dartmouth College; Technische Universität Dresden; Centre National de la Recherche Scientifique, France
• Investigators: Principal Investigator: Martin Picard, PhD, Columbia University

Publications and helpful links

Helpful Links

• Study Brochure

Study record dates

Study Major Dates

• Study Start (Actual): June 12, 2018
• Primary Completion (Actual): June 30, 2023
• Study Completion (Actual): May 3, 2024

Study Registration Dates

• First Submitted: March 31, 2021
• First Submitted That Met QC Criteria: April 1, 2021
• First Posted (Actual): April 5, 2021

Study Record Updates

• Last Update Posted (Estimated): May 20, 2025
• Last Update Submitted That Met QC Criteria: May 10, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Stress; Mitochondria; Brain Imaging; Epigenetics; Mitochondrial function; Psychophysiology; Metabolic rate
• Additional Relevant MeSH Terms: Metabolic Diseases; Mitochondrial Diseases
• Other Study ID Numbers: NYSPI 7424; 5R01MH122706 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All data will be deposited to the NIMH Data Archive.
• IPD Sharing Time Frame: Data will be made available at the end of the study, without a expiry date.
• IPD Sharing Access Criteria: Access will be handled through the NIMH Data Archive (NDA)
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

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