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Adaptive Neuromodulation of Working Memory Networks in Aging and Dementia

Award Number: R01AG075417
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Adaptive Neuromodulation of Working Memory Networks in Aging and Dementia - PROJECT SUMMARY Dementia due to Alzheimer’s disease (AD) is a leading public health concern in the US with enormous care costs and no effective pharmacotherapy despite multiple clinical trials. Multiple studies have shown mild cognitive impairment (MCI) to be a precursor risk for AD and to be more amenable to intervention. While preclinical studies have shown that directly modulating activity in the prefrontal cortex (PFC) using non-invasive brain stimulation techniques, such as transcranial magnetic stimulation (TMS), can modulate cognitive function in healthy older adults, there is little evidence of reliable efficacy in MCI. We posit three reasons for this lack of efficacy. First, there is no established means of estimating a reliable biomarker as well as a unique dose-response relationship between TMS intensity and brain activity, which remains a fundamental means of titrating individualized response to neuromodulation. Second, standard TMS protocols fail to capture the dynamic nature of cognitive states and the reaction of endogenous brain states to exogenous neuromodulation. By understanding the dynamic changes associated with a successful brain state, it should be possible to manipulate PFC dynamically in a manner that enhances cognition. Third, no studies using TMS in AD-related populations have accounted for the influence of cerebrovascular disease in the response to TMS. We propose to address these shortcomings by using closed-loop TMS, based on individualized brain networks to establish parameters that can reliably control brain states during normal memory functioning in healthy aging and MCI. To achieve this goal, we will study network activation and neural oscillatory mechanisms underlying the network that regulates working memory (WM), a cognition function with a reliable PFC-based network characterization. We will then target this network using closed-loop TMS to the PFC and measure the impact on WM performance and task-based neural activity. This approach, which builds on our existing K01, U01, and RF1 awards, uses concurrent TMS-fMRI to identify dose-response relationships in the working memory network, which can be used to identify neuroplasticity and optimize targeting for TMS (Aim 1). Next, we apply novel closed-loop TMS to perturb this network using temporally-precise TMS-EEG (Aim 2), optimizing the encoding of memory by minimizing endogenous alpha oscillations. Lastly, we will integrate information collected via fMRI and EEG into a single computational framework in order to model spatiotemporal dynamics of the global brain network, accounting for the influence of both connectivity and cerebrovascular pathology in predicting the success of the TMS-related response in our MCI cohort (Aim 3). In sum, the project will use cutting-edge brain stimulation and network modeling techniques to enhance WM in healthy older adults and MCI and will provide a demonstration of the value of closed-loop, network-guided TMS for future clinical applications.


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 = $361,791 )
2026	2026	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Aging Research	003	5	8/14/2026	NON-COMPETING CONTINUATION	$548,484
2026	2024	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Aging Research	001	4	4/13/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$520,523
2026	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Aging Research	000	3	4/9/2026	NON-COMPETING CONTINUATION	-$707,216
2026	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Aging Research	002	3	5/12/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $361,791

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Aging Research	000	3	7/15/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $735,845 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Aging Research	001	3	7/10/2024	NON-COMPETING CONTINUATION	$735,845
2024	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Aging Research	000	2	11/8/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $735,845

Issue Date FY: 2023 ( Subtotal = $754,374 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Aging Research	000	2	8/11/2023	NON-COMPETING CONTINUATION	$754,374
														Subtotal = $754,374

Issue Date FY: 2022 ( Subtotal = $733,471 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Aging Research	000	1	9/9/2022	NEW	$733,471
														Subtotal = $733,471

Grand Total All Awards = $2,585,481

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Adaptive Neuromodulation of Working Memory Networks in Aging and Dementia

Award Number: R01AG075417

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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