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Completed

NCT Number: NCT03896659

Exploring the Effects of Corticosteroids on the Human Hippocampus

Chronic corticosteroid (CS) exposure is associated with changes in memory and the hippocampus in both humans and in animal models. The hippocampus has a high concentration of glucocorticoid receptors (GCRs), and the pre-clinical literature demonstrates shortening of apical dendrites in the CA3 region of the hippocampus and decreased neurogenesis in the dentate gyrus (DG) following CS administration. In humans, both stress and CS exposure are associated with a decline in declarative memory performance (a process mediated by the hippocampus). Impairment in declarative memory and hippocampal atrophy are reported in patients with excessive CS release due to Cushing's disease, and, by our group, in patients receiving prescription CS therapy. These findings have important implications for patients with mood disorders, as a large subset of people with major depressive disorder (MDD) show evidence of HPA axis activation, elevated cortisol and, importantly, resistance to the effects of CSs on both the HPA axis and on declarative memory. Thus, resistance to corticosteroids appears to be a consequence of MDD.

this study will examine changes in declarative memory, as well as use state-of-the-art high-resolution multimodal neuroimaging, including structural and functional (i.e., task-based and resting state) MRI, in both men and women healthy controls, and, as an exploratory aim, a depressed group, given 3-day exposures to hydrocortisone (160 mg/day) or placebo. The study will translate preclinical findings to humans, provide valuable data on possible sex differences in the response to cortisol and, for the first time, identify specific hippocampal subfields (e.g., CA3/DG) in humans that are most sensitive to acute CS effects. Using resting state fMRI data and whole brain connectomics using graph theoretical approaches, we will determine the effects of cortisol exposure on functional brain networks. Furthermore, this will be the first study to use neuroimaging to compare the brain's response to CSs in people with depression vs. controls, and determine whether depressed people demonstrate glucocorticoid resistance within the hippocampus. We hypothesize that hippocampal response to acute CSs will be greatest in the CA3/DG subfield, greater in women than in men, and that depressed people will show a blunted hippocampal response to CSs compared to controls. A multidisciplinary research team with extensive experience in CS effects on the brain and hippocampal subfield neuroimaging, and a prior history of research collaboration, will conduct the project.

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Key information

Conditions

Hydrocortisone Behavior Behavioral Symptoms Depression Healthy Volunteers

Age range

18 year–50 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Men and women age 18-50 years with vision corrected to at least 20-40 (needed for fMRI tasks)
  • Education of ≥ 12 years
  • Baseline RAVLT total words recalled T-score ≥ 40 (normal range)
  • BMI between 18.5-35.0 (neither underweight nor severely obese)
  • Baseline QIDS-C ≤ 5 (virtual absence of depressive symptoms) for "healthy controls" and for the "depressed" group a QIDS-C between 11-20 (≥ moderate depressive symptoms but < very severe depressive symptoms)

Exclusion criteria

  • History of major psychiatric illness other than MDD for the depressed group, defined as bipolar disorder, posttraumatic stress disorder, schizoaffective disorder, schizophrenia, eating disorders, or MDD with psychotic features. For the control group, a past episode of MDD (per SCID) is also exclusionary
  • History of drug or alcohol use disorder
  • History of neurological disorders including seizures, brain surgery, multiple sclerosis, Parkinson's disease
  • Taking CNS-acting medications (e.g., antidepressants, antipsychotics, lithium, anticonvulsants, sedative/hypnotic/anxiolytics). Thus, the depressed group will be medication free.
  • History of allergic reaction or medical contraindication to hydrocortisone
  • Metal implants, claustrophobia, or other contraindications to MRI
  • Significant medical conditions (e.g., cancer, heart disease, diabetes)
  • Vulnerable population including pregnant or nursing women, prisoners, and people with intellectual disability, history of special education classes, dementia, or other severe cognitive disorders
  • Current suicidal ideation, a suicide attempt in the past 12 months or more than one lifetime attempt
  • History of systemic CS use in the past 12 months, lifetime cumulative use of more than 12 weeks, or recent (defined as past 28 days) inhaled CS use
  • Women who are using estrogen containing oral contraceptive agents (other contraceptives are acceptable, see Protection of Human Subjects section for a list of acceptable birth control methods) or who are post- or peri-menopausal or with irregular menstrual cycles (i.e., inconsistent menstruation patterns)

Treatment and study plan

Hydrocortisone Oral

Drug

Hydrocortisone 160 mg tablet

Placebo oral tablet

Drug

Hydrocortisone-matched Placebo tablet

Primary outcomes

  1. Hippocampal Subfield Activation (Left Hemisphere)

    Time frame: 3 days

    The z-scores of hippocampal subregions and hemispheres represent the standardized difference in activation between correct and incorrect conditions of the mnemonic discrimination task, where a Z-score of 0 represents the mean difference across all voxels, and each unit reflects one standard deviation from that mean. To compare brain activation between conditions, separate beta weights were estimated for correct and incorrect trials across all trials. These beta weights represent the voxel-wise blood oxygen level (BOLD)-dependent signal, reflecting changes in neural activity associated with each condition. Positive z-scores indicate greater activation for correct relative to incorrect trials, whereas negative z-scores indicate greater activation for incorrect relative to correct trials. Larger absolute z-scores indicate stronger condition-related effects; there are no established clinical thresholds for these experimental activation differences.

  2. Hippocampal Subfield Activation (Right Hemisphere)

    Time frame: 3 days

    The z-scores of hippocampal subregions and hemispheres represent the standardized difference in activation between correct and incorrect conditions of the mnemonic discrimination task, where a Z-score of 0 represents the mean difference across all voxels, and each unit reflects one standard deviation from that mean. To compare brain activation between conditions, separate beta weights were estimated for correct and incorrect trials across all trials. These beta weights represent the voxel-wise blood oxygen level (BOLD)-dependent signal, reflecting changes in neural activity associated with each condition. Positive z-scores indicate greater activation for correct relative to incorrect trials, whereas negative z-scores indicate greater activation for incorrect relative to correct trials. Larger absolute z-scores indicate stronger condition-related effects; there are no established clinical thresholds for these experimental activation differences.

  3. Hippocampal Subfield Volume (Left Hemisphere)

    Time frame: 3 days

    High resolution structural neuroimaging will be used to generate regional hippocampal subfield volume.

  4. Hippocampal Subfield Volume (Right Hemisphere)

    Time frame: 3 days

    High resolution structural neuroimaging will be used to generate regional hippocampal subfield volume.

Sponsors and collaborators

Lead sponsor

University of Texas Southwestern Medical Center

Other

Collaborators

  • National Institute of Mental Health (NIMH)
  • University of California, Irvine

Registry information

Official study title

Exploring the Effects of Corticosteroids on the Human Hippocampus Using Neurocognitive Testing and High Resolution Neuroimaging

Important dates

Study start
2019
Primary completion
2024
Study completion
2024
First posted
Apr 1, 2019
Registry last updated
Dec 16, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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