The Functional Neuroanatomy of the Human Physiological Stress Response

Study Overview
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Brief Summary
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The purpose of this study is to examine the effect of a moderately low blood sugar stress on the nervous system. The investigators hope that information obtained from completing this study will help to reveal information about how a non-psychological stress impacts the parts of the brain that react to stress and the autonomic nervous system. The autonomic nervous system is the part of the nervous system that provides the body with involuntary or automatic control of heart rate, blood pressure, and breathing.

Detailed Description
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Stress is common in daily life and is associated with adverse health outcomes. This proposal will study how a physiological stress (low blood sugar), a stress often experienced by people with diabetes, affects connections in the brain. The investigators will focus on brain connections that are involved in autonomic control of cardiovascular function, and determine both how these brain connections are altered by low blood sugar and how these alterations associate with changes in pain perception and cardiovascular control. In this study, the investigators introduce a novel mechanistic, integrative approach to the assessment of the response to and recovery from a specific physiologic stressor - insulin-induced hypoglycemia. The overall hypothesis is that a hypoglycemic stress will alter autonomic brain networks, and will affect clinically relevant physiological outcomes (cardiovascular autonomic function); and that the rate and extent of recovery of these brain networks will provide a measure of resilience. In combination, this approach will allow the investigators for the first time to define the magnitude of the effect of stress exposure on neural circuitry and on clinically relevant stress-related physiological outcomes (cardiovascular autonomic function) and to define the recovery of brain circuitry and these related physiological outcomes.

Official Title
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The Functional Neuroanatomy of the Human Physiological Stress Response

Conditions
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Hypoglycemia, Physiological Stress

Intervention / Treatment
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* Other: Hypoglycemic Hyperinsulinemic Clamp
* Other: Normoglycemic Hyperinsulinemic Clamp


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy volunteers Males and Females age 18 to 45 years BMI 18-35 kg/m2 Exclusion Criteria: Pregnancy Lactation Menopause Any medical condition Current or prior alcohol or drug abuse Active tobacco use Abnormal ECG In all subjects, any individuals on oral, injected, inhaled or topical corticosteroids within the last year or oral contraceptives within the past 3 months will be excluded. Use of medications other than thyroid hormone or hormonal birth control Serum potassium >5.0 mmol/L Estimated GFR <60 mL/min/1.73 m2 Hemoglobin A1c ≥6.5% Patient Health Questionnaire (PHQ9) for depression score ≥15 GAD-7 Questionnaire for anxiety score ≥10 PTSD Checklist for DSM-5 (PCL-5) score ≥31 Perceived Stress Scale (PSS-14) score >28 Blood pressure systolic ≥140 or <100 mmHg; Blood pressure diastolic >90 mmHg Metal in the body including: cardiac pacemakers, stents, artificial heart valves, artificial limbs or hands, brain stimulator devices, implanted drug pumps, ear implants, eye implants or known metal fragments in eyes, exposure to shrapnel or metal filings (wounded in military combat, sheet metal workers, welders, and others), other metallic surgical hardware in vital areas, certain tattoos with metallic ink, certain transdermal medication patches, and metal-containing IUDs

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Hypoglycemia<br>Participants undergo Autonomic Nervous System (ANS) Testing (measurement of Baroreflex Sensitivity using the Modified Oxford test) followed by a functional MRI (fMRI) scan. The next day, participants undergo one 120-minute hypoglycemic hyperinsulinemic clamp procedure (50mg/dL) in the morning followed by ANS Testing and an fMRI scan. Four days later, participants undergo repeat ANS Testing and an fMRI scan. | Other: Hypoglycemic Hyperinsulinemic Clamp<br>* Participants undergo a 120-minute hypoglycemic hyperinsulinemic clamp procedure.<br>* Other names: Hypoglycemic Hyperinsulinemic Clamp Procedure;|
| Placebo Comparator: Normoglycemia<br>Participants undergo Autonomic Nervous System (ANS) Testing (measurement of Baroreflex Sensitivity using the Modified Oxford test) followed by a functional MRI (fMRI) scan. The next day, participants undergo one 120-minute normoglycemic hyperinsulinemic clamp procedure (90mg/dL) in the morning followed by ANS Testing and an fMRI scan. Four days later, participants undergo repeat ANS Testing and an fMRI scan. | Other: Normoglycemic Hyperinsulinemic Clamp<br>* Participants undergo a 120-minute normoglycemic hyperinsulinemic clamp procedure.<br>* Other names: Normoglycemic Hyperinsulinemic Clamp Procedure;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of physiological stress (hypoglycemia) on brain networks involved in autonomic function | Functional MRI will be performed following physiological stress (hypoglycemia) or placebo (normoglycemia) and a functional connectivity analysis will be performed on the fMRI data. The outcome will be alterations in neural network connectivity, as measured by changes in Pearson-correlation coefficients among the following brain structures: right anterior insula and anterior cingulate cortex; right anterior insula and hypothalamus; hypothalamus and anterior cingulate cortex; hypothalamus and amygdala; locus coeruleus and hypothalamus. | Baseline, 8 hours after physiological stress, and 4 days after physiological stress | 
| The relationship over time between stress-induced changes in brain networks and stress-induced changes in baroreflex sensitivity | The stress-induced change in baroreflex sensitivity (msec/mmHg) will be determined. Pearson correlation coefficients (r) between the changes in baroreflex sensitivity and the changes in brain connectivity (right anterior insula and anterior cingulate cortex; hypothalamus and amygdala [determined for the first outcome above]) will be calculated and tested for significance. | Baseline, 8 hours after physiological stress, and 4 days after physiological stress | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypoglycemia, Stress, Brain