# Early Life Stress and Depression: Molecular and Functional Imaging Approaches

> **NIH NIH R01** · MCLEAN HOSPITAL · 2020 · $819,579

## Abstract

Project Summary
Epidemiological studies have shown that severe childhood adversity explains 32-44% of psychiatric disorders,
and is associated with 4.6-fold risk for depression and 6.6-fold risk for substance abuse later in life. In spite of
these epidemiological data, the neurobiological underpinnings associated with maladaptive sequelae of CSA
remain largely unknown. Preclinical research strongly suggests that early adversity leads to (1) structural
abnormalities in medial prefrontal cortex regions critically implicated in stress regulation; (2) increased
oxidative stress; and (3) glutamatergic abnormalities. The current competing renewal was specifically designed
to prospectively test the contributions of these abnormalities in individuals exposed to CSA. Together, these
studies will test the hypotheses that abnormalities within “immuno-oxidative” mechanisms, including abnormal
balance of redox regulation, oxidative stress and glutamate metabolites are linked to MDD and CSA
pathophysiology. We expect that interactions among these abnormalities (1) lead to excitatory/inhibitory
imbalance of local neuronal circuits and morphometrical abnormalities within key regions (mPFC); (2) are
associated with key MDD phenotypes; and (3) prospectively predict future symptoms and functioning. These
goals will be achieved by evaluating young adult females with a history of CSA between the ages of 12-16
years with a current (“MDD/CSA” group) or former (“rMDD/CSA” group) diagnosis of major depressive
disorder. To disentangle CSA- vs. MDD-related effects, these groups will be compared to both healthy controls
and MDD females without a history of CSA (“MDD” group). All subjects (N=160) will be tested at both 3T and
4T scanners using an integration of state-of-the-art 31P magnetic resonance spectroscopy (MRS) (to quantify
redox ratio and brain bioenergetics in vivo), high field multinuclear MRS (to assess glutamate metabolites and
glutathione), functional magnetic resonance imaging (to probe the neural correlates of anhedonic behavior and
cognitive control deficits). To track disease course, all participants will be prospectively assessed at 6- and 12-
month follow-up sessions. Based on our extensive set of preliminary findings, we hypothesize that, relative to
both healthy controls and the MDD group, MDD/CSA individuals will show greater cortical thinning in the
medial prefrontal cortex, lower redox ratio, lower glutamine/glutamate ratio, and higher inflammatory markers
(Hypothesis 1). We further expect that these abnormalities will persist in euthymic rMDD/CSA subjects,
particularly with increasing number of lifetime depressive episodes. Moreover, we expect that these
abnormalities will be associated with increased anhedonic behavior and cognitive deficits (Hypotheses 2), and
will predict anhedonic symptom, cognitive deficits and poorer general functioning at the follow-up assessments
(Hypothesis 3). Improving our understanding of neurobiological mechanisms assoc...

## Key facts

- **NIH application ID:** 10049698
- **Project number:** 2R01MH095809-05A1
- **Recipient organization:** MCLEAN HOSPITAL
- **Principal Investigator:** FEI DU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $819,579
- **Award type:** 2
- **Project period:** 2012-09-18 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10049698

## Citation

> US National Institutes of Health, RePORTER application 10049698, Early Life Stress and Depression: Molecular and Functional Imaging Approaches (2R01MH095809-05A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10049698. Licensed CC0.

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