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| ID | Type | Description | Link |
|---|---|---|---|
| 5R01MH122706 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| Dartmouth College | OTHER |
| Centre National de la Recherche Scientifique, France | OTHER |
| Massachusetts General Hospital | OTHER |
| Technische Universität Dresden |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Healthy controls | Experimental | No diagnosis of mitochondrial disease |
|
| Mutation | Experimental | Participants carrying the m.3243A>G point mutation, without a diagnosis of MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) |
|
| Mutation with MELAS | Experimental | Participants carrying the m.3243A>G point mutation, with a diagnosis of MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) |
|
| Deletion | Experimental | Participants carrying a single, large-scale mtDNA deletion |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Trier social stress test | Behavioral | 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. |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Martin Picard, PhD | Columbia University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Columbia University Irving Medical Center | New York | New York | 10032 | United States |
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| Label | URL |
|---|---|
| Study Brochure | View source |
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All data will be deposited to the NIMH Data Archive.
Data will be made available at the end of the study, without a expiry date.
Access will be handled through the NIMH Data Archive (NDA)
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| ID | Title | Description |
|---|---|---|
| FG000 | Healthy Controls | No diagnosis of mitochondrial disease |
| FG001 | Mutation | Participants carrying the m.3243A>G point mutation, without a diagnosis of MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) |
| FG002 | Deletion | Participants carrying a single, large-scale mtDNA deletion |
| FG003 | Mutation With MELAS | Participants carrying the m.3243A>G point mutation, with a diagnosis of MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Healthy Controls | No diagnosis of mitochondrial disease |
| BG001 | Mutation | Participants carrying the m.3243A>G point mutation, without a diagnosis of MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Posted | Mean | Standard Deviation | ng*min/mL | Day 1 post challenge (approximately 2 hours) |
|
2 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Healthy Controls | No diagnosis of mitochondrial disease | 0 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Martin Picard | Columbia University | 6467748967 | mp3484@columbia.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Oct 6, 2023 | Feb 4, 2025 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Oct 6, 2023 | Feb 4, 2025 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D028361 | Mitochondrial Diseases |
| ID | Term |
|---|---|
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D011581 | Psychological Tests |
| ID | Term |
|---|---|
| D004191 | Behavioral Disciplines and Activities |
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| OTHER |
| National Institute of Mental Health (NIMH) | NIH |
All participants will undergo TSST and have samples With DNA collected (blood plasma and serum, purified leukocytes, saliva, urine, buccal epithelial cells, hair are stored).
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|
|
| 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 |
| BG002 | Deletion | Participants carrying a single, large-scale mtDNA deletion |
| BG003 | Mutation With MELAS | Participants carrying the m.3243A>G point mutation, with a diagnosis of MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG002 | Deletion | Participants carrying a single, large-scale mtDNA deletion |
| OG003 | Mutation With MELAS | Participants carrying the m.3243A>G point mutation, with a diagnosis of MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) |
|
|
| Primary | 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. | Posted | Mean | Standard Deviation | allostatic load score | Blood collected on Day 1 |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | beats per minute | Baseline and 2 hours post challenge on Day 1 |
|
|
|
| Secondary | 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. | Posted | Number | coefficient of determination (R^2) | Day 1 |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | Z-score | Day 2 neuropsychological session |
|
|
|
| 70 |
| 0 |
| 70 |
| 0 |
| 70 |
| EG001 | Mutation | Participants carrying the m.3243A>G point mutation, without a diagnosis of MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) | 0 | 20 | 0 | 20 | 0 | 20 |
| EG002 | Deletion | Participants carrying a single, large-scale mtDNA deletion | 0 | 15 | 0 | 15 | 0 | 15 |
| EG003 | Mutation With MELAS | Participants carrying the m.3243A>G point mutation, with a diagnosis of MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) | 0 | 5 | 0 | 5 | 0 | 5 |
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| Correlation between mitochondrial respiration and trait anxiety |
|