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Lithium Effects on the Brain's Functional and Structural Connectome in the Treatment of Bipolar Disorder

Award Number: R01MH113256
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2017
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Lithium Effects on the Brain's Functional and Structural Connectome in the Treatment of Bipolar Disorder - ABSTRACT Lithium is one of the most specific and effective treatments for bipolar disorder (BD) yet its mechanism of action remains unclear. This has impeded methods to monitor its effects and the development of new medications with similar efficacy and specificity. Clinical efficacy of lithium in bipolar disorder, and its complex effects on multiple brain physiological functions, may be best deciphered using a network properties-metric approach. This approach is critical because it provides insight into the function of brain networks (e.g., resilience to disruption, central hubs), which is likely to be more closely linked to behavioral outcomes. Furthermore, the relationship of the neuroimaging effects of lithium and its molecular effects in humans has been studied even less. This proposal addresses these important gaps in knowledge by measuring brain functional and structural connectomics before and after acute and longer term treatment with lithium. We will study 90 medication free bipolar disorder depressed (BDD) type II subjects at baseline and after 2, 8 and 26 weeks of lithium monotherapy. We will also study 30 closely matched healthy controls who will be imaged at the same time points but will not receive any treatment. BDD II subjects will undergo resting state functional magnetic resonance imaging (fMRI) scans and diffusion weighted structural imaging scans. In addition to imaging, we will also collect RNA samples from peripheral blood lymphocytes to explore lithium induced peripheral gene expression changes. Functional and structural scans will be analyzed using graph theory metrics (GTM) and Independent Component Analysis (ICA). Graph theory metrics move beyond simple description of brain connectivity and provide insight into network function (e.g., resilience to disruption, regional hubs). ICA analysis has identified consistent and well defined independent components in resting state data e.g the default mode and salience networks. Preliminary data from our studies indicates significant effect of lithium on GTM and ICA metrics and correlation of the changes in these metrics to clinical improvement. In this proposal, we will acquire images on a state-of-the-art 7-T scanner, conduct rigorous motion correction and apply cutting-edge GTM and ICA analytics. We will correlate changes in GTA and ICA metrics to improvement in depression in the short term and mood stability in the longer term in BDD II subjects. Furthermore, we will conduct an exploratory analysis regarding association between changes in peripheral gene expression and improvement in symptomatology and mood stability using the GTA metrics change as mediators and using ICA multimodality fusion analysis. This will be an exploratory analysis to yield data for future more definitive human and basic science studies of lithium effect. This study will therefore provide unique data regarding imaging and molecular correlates of lithium monotherapy and its relationship to lithium efficacy in bipolar disorder. In addition, this study will provide a novel paradigm to investigate effects of lithium and other psychotropics using network-property metrics as biomarkers which can be used for treatment monitoring and drug development.


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: 2026 ( Subtotal = -$28,885 )
2026	2021	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	5	11/20/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$28,885
														Subtotal = -$28,885

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	5	6/13/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	008	5	6/2/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2021	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	009	5	6/26/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2021	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	007	5	11/30/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,587,188
2023	2021	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	003	5	11/16/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$1,587,187
2023	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Mental Health Research Grants	002	4	11/16/2022	NON-COMPETING CONTINUATION	$731,216
2023	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Mental Health Research Grants	006	4	11/30/2022	NON-COMPETING CONTINUATION	-$731,216
2023	2019	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Mental Health Research Grants	005	3	11/30/2022	NON-COMPETING CONTINUATION	-$726,938
2023	2019	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Mental Health Research Grants	001	3	11/16/2022	NON-COMPETING CONTINUATION	$726,938
2023	2018	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Mental Health Research Grants	000	2	11/16/2022	NON-COMPETING CONTINUATION	$129,033
2023	2018	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Mental Health Research Grants	004	2	11/30/2022	NON-COMPETING CONTINUATION	-$129,034
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	003	5	1/11/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,587,187
2022	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Mental Health Research Grants	002	4	1/10/2022	NON-COMPETING CONTINUATION	-$731,216
2022	2019	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Mental Health Research Grants	001	3	1/10/2022	NON-COMPETING CONTINUATION	-$726,938
2022	2018	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Mental Health Research Grants	000	2	1/10/2022	NON-COMPETING CONTINUATION	-$129,033
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $741,043 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	001	5	8/18/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$741,043
2021	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Mental Health Research Grants	000	4	8/18/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $741,043

Issue Date FY: 2020 ( Subtotal = $731,216 )
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Mental Health Research Grants	000	4	4/16/2020	NON-COMPETING CONTINUATION	$731,216
														Subtotal = $731,216

Issue Date FY: 2019 ( Subtotal = $726,938 )
2019	2019	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Mental Health Research Grants	000	3	4/26/2019	NON-COMPETING CONTINUATION	$726,938
														Subtotal = $726,938

Issue Date FY: 2018 ( Subtotal = $726,938 )
2018	2018	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Mental Health Research Grants	000	2	4/23/2018	NON-COMPETING CONTINUATION	$726,938
														Subtotal = $726,938

Issue Date FY: 2017 ( Subtotal = $782,595 )
2017	2017	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Mental Health Research Grants	000	1	6/27/2017	NEW	$782,595
														Subtotal = $782,595

Grand Total All Awards = $3,679,845

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Lithium Effects on the Brain's Functional and Structural Connectome in the Treatment of Bipolar Disorder

Award Number: R01MH113256

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2017

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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