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Early Life Stress and Depression: Molecular and Functional Imaging Approaches

Award Number: R01MH095809
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/18/2012
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Early Life Stress and Depression: Molecular and Functional Imaging Approaches - 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 associated with different CSA outcomes is of paramount importance in order to (1) identify individuals at risk for psychopathology and maladaptive behavior, (2) prevent revictimization, and (3) develop more targeted therapeutic interventions.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	THE MCLEAN HOSPITAL CORPORATION	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	9	3/8/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $778,023 )
2024	2024	THE MCLEAN HOSPITAL CORPORATION	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	9	5/15/2024	NON-COMPETING CONTINUATION	$778,023
														Subtotal = $778,023

Issue Date FY: 2023 ( Subtotal = $778,984 )
2023	2023	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	8	4/14/2023	NON-COMPETING CONTINUATION	$778,984
														Subtotal = $778,984

Issue Date FY: 2022 ( Subtotal = $774,310 )
2022	2022	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	7	5/2/2022	NON-COMPETING CONTINUATION	$774,310
														Subtotal = $774,310

Issue Date FY: 2021 ( Subtotal = $772,752 )
2021	2021	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	6	6/4/2021	NON-COMPETING CONTINUATION	$772,752
														Subtotal = $772,752

Issue Date FY: 2020 ( Subtotal = $819,579 )
2020	2020	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	001	5	7/13/2020	COMPETING CONTINUATION	$0
2020	2020	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	5	6/26/2020	COMPETING CONTINUATION	$819,579
														Subtotal = $819,579

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2016	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	4	8/22/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $574,641 )
2016	2016	MCLEAN HOSPITAL	115 MILL STREET	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	4	5/13/2016	EXTENSION WITH OR WITHOUT FUNDS	$574,641
														Subtotal = $574,641

Issue Date FY: 2015 ( Subtotal = $730,579 )
2015	2015	MCLEAN HOSPITAL	115 MILL STREET	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	001	3	8/19/2015	SUPPLEMENT FOR EXPANSION	$155,832
2015	2015	MCLEAN HOSPITAL	115 MILL STREET	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	3	5/7/2015	NON-COMPETING CONTINUATION	$574,747
														Subtotal = $730,579

Issue Date FY: 2014 ( Subtotal = $0 )
2014	2013	MCLEAN HOSPITAL	115 MILL STREET	BELMONT	MA	02178		USA	Mental Health Research Grants	000	2	6/21/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = $539,307 )
2013	2013	MCLEAN HOSPITAL	115 MILL STREET	BELMONT	MA	02178		USA	Mental Health Research Grants	001	2	7/18/2013	NON-COMPETING CONTINUATION	$0
2013	2013	MCLEAN HOSPITAL	115 MILL STREET	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	2	6/13/2013	NON-COMPETING CONTINUATION	$539,307
														Subtotal = $539,307

Issue Date FY: 2012 ( Subtotal = $646,824 )
2012	2012	MCLEAN HOSPITAL	115 MILL STREET	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	1	9/15/2012	NEW	$646,824
														Subtotal = $646,824

Grand Total All Awards = $6,414,999

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Early Life Stress and Depression: Molecular and Functional Imaging Approaches

Award Number: R01MH095809

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/18/2012

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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