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Elucidating neural mechanisms of hypo/mania using theta burst stimulation

Award Number: R01MH122990
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2020
PERIOD OF PERFORMANCE END DATE: 10/31/2025

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Elucidating neural mechanisms of hypo/mania using theta burst stimulation - ABSTRACT. Bipolar Disorder (BD), defined by a history of hypo/mania, is common and debilitating. Yet, the neural mechanisms predisposing to hypo/mania, to guide new interventions for BD, are poorly understood. BD is characterized by abnormally elevated reward sensitivity, impulsivity and sensation seeking, response tendencies that predispose to hypo/mania in potentially rewarding contexts, e.g., uncertain reward expectancy (RE). In adults with BD, we reported abnormally elevated uncertain RE-related left ventrolateral prefrontal cortical (vlPFC) activity. Moreover, we showed a positive relationship between RE-related left vlPFC activity and an impulsivity component, negative urgency; and that negative urgency mediates a positive association between RE-related left vlPFC activity and the severity of lifetime predisposition to hypo/mania in young adults who have not yet developed BD. Abnormally elevated left vlPFC activity to RE is thus a potential neural mechanism underlying heightened negative urgency, which confers risk for development of/ worsening hypo/mania. Theta- burst stimulation (TBS) is a Repetitive Transcranial Magnetic Stimulation (rTMS) paradigm that can acutely, rapidly, and non-invasively modulate the left vlPFC. Examining if continuous (inhibitory) TBS (cTBS) over left vlPFC leads to acute changes in hypo/mania-related affect is thus a first step toward elucidating the neural mechanisms that predispose to hypo/mania. We will recruit 50 remitted/mild-moderate hypomanic adults with BD type I (in whom we reported the majority of RE-related neuroimaging data): 18-35 yrs (unmedicated/ on common BD medications), to avoid confounds of long psychiatric illness/ long medication history; and 50 age- and gender ratio-matched healthy/ non BD (history of anxiety/ non BD mood disorders) adults. We will examine activity in and functional connectivity (FC) among left vlPFC and reward regions: ventral striatum (VS), amygdala, orbitofrontal cortex (OFC) and dorsal/rostral anterior cingulate cortex (d/rACC). Each participant will have baseline assessments of negative urgency (and other BD-related response tendencies) and a baseline structural scan for neurotargeting and TBS dose thresholding. One week later, there will be 3 scan sessions over <2 weeks: each with 1 of 3 TBS conditions interleaved between pre and post cTBS scans, in randomized order: left vlPFC cTBS; left control region, somatosensory cortex, cTBS; and left vlPFC sham TBS. Positive and negative affect will be measured before each pre cTBS and after each post cTBS scan. We aim to: 1. Determine the impact of acute cTBS over left vlPFC (vs. other cTBS conditions) on RE-related activity in and FC among left vlPFC, VS, amygdala, d/rACC, OFC; 2. Determine if cTBS-induced neural changes lead to acute changes in hypo/mania- related affect, and if negative urgency moderates these relationships; 3. Compare effects of cTBS over left vlPFC (vs. other conditions) on neural-affect measures in BD vs. healthy/ non BD adults. We will explore whether other BD-related response tendencies moderate cTBS-induced neural-affect changes. We will examine the acute impact of cTBS on reward circuitry and affect, to elucidate neural mechanisms that predispose to hypo/mania.


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 = $593,272 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Mental Health Research Grants	000	5	12/4/2024	NON-COMPETING CONTINUATION	$593,272
														Subtotal = $593,272

Issue Date FY: 2024 ( Subtotal = $745,244 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Mental Health Research Grants	000	4	4/9/2024	NON-COMPETING CONTINUATION	$670,721
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Mental Health Research Grants	001	4	4/30/2024	NON-COMPETING CONTINUATION	$74,523
														Subtotal = $745,244

Issue Date FY: 2023 ( Subtotal = $670,722 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Mental Health Research Grants	001	3	1/19/2023	NON-COMPETING CONTINUATION	$67,073
2023	2023	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Mental Health Research Grants	000	3	11/7/2022	NON-COMPETING CONTINUATION	$603,649
														Subtotal = $670,722

Issue Date FY: 2022 ( Subtotal = $702,051 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Mental Health Research Grants	001	2	6/7/2022	NON-COMPETING CONTINUATION	$70,208
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Mental Health Research Grants	000	2	10/22/2021	NON-COMPETING CONTINUATION	$631,843
														Subtotal = $702,051

Issue Date FY: 2021 ( Subtotal = $746,515 )
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Mental Health Research Grants	001	1	5/4/2021	NEW	$0
2021	2021	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Mental Health Research Grants	000	1	11/25/2020	NEW	$746,515
														Subtotal = $746,515

Grand Total All Awards = $3,457,804

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Elucidating neural mechanisms of hypo/mania using theta burst stimulation

Award Number: R01MH122990

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2020

PERIOD OF PERFORMANCE END DATE: 10/31/2025

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