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Elucidating the Temporality of Structural and Functional Connectivity Changes in Essential Tremor after successful Deep Brain Stimulation to the dentato-rubrothalamic tract

Award Number: R01NS113893
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Elucidating the Temporality of Structural and Functional Connectivity Changes in Essential Tremor after successful Deep Brain Stimulation to the dentato-rubrothalamic tract - Project Summary The symptoms of Essential Tremor (ET), the most common movement disorder in adults, are seriously disabling and are only marginally improved by medication alone. Tremor control has improved greatly with the use of deep brain stimulation (DBS) to the ventrointermediate nucleus (Vim) of the thalamus, a node along a circuit of abnormal rhythmic output in ET that travels from the cerebellar dentate nucleus to the contralateral red nucleus and cortex via the dentato-rubro-thalamic tract (DRTt). Recent advances in diffusion imaging have led to the development of tractography techniques where the structural connectivity of fiber tracts such as the DRTt can be illustrated and then, as we have shown, directly targeted during DBS surgery for excellent clinical effect. Despite such novel targeting methodology and initial tremor improvement, however, the development of side effects such as progressive gait ataxia and waning efficacy after years of chronic stimulation points to the fact that the pathology of essential tremor is poorly understood. Such incomplete knowledge of the network effects of chronic stimulation in ET is a major barrier that needs to be overcome through understanding the dysfunction and modulation of the connectivity of the cerebellar-thalamic-cortical (CTC) network over time. Resting state functional MRI (rsfMRI) has emerged as a powerful tool to explore the functional connectivity between different brain regions and has improved the idea of ET as a network-based disease not confined to the motor circuit, including parietal visuomotor processing cortices; however, comparisons pre- and post- DBS have not been performed. The use of positron emission tomography (PET) has correlated ataxic side effect with cerebellar metabolic changes after chronic DBS; however, associated changes seen with rsfMRI are unknown. Our long-term goal is to understand how stimulation of the DRTt causes network-level effects over time. Our central hypothesis is that structural and functional connectivity of the DRTt correlates with clinical response to DBS in a time-dependent fashion. In pursuit of this hypothesis, we will recruit new ET patients already undergoing DBS and additionally perform imaging analysis to elucidate the effects of stimulation and define DRTt connectivity. In Aim 1, we seek to define the structural connectivity of the DRTt by using tractography methods and compare over time diffusivity changes correlated with clinical response and/or ataxic side effect. In Aim 2, we seek to detect functional network changes due to DBS by using rsfMRI obtained serially in ON/OFF states, where we will track the evolution of altered connectivity changes over time. In Aim 3, we seek to confirm the cortical mediators of tremor identified in Aims 1 and 2 by use of intraoperative electrocorticography during DBS. This innovative combination of using a novel targeting technique and serial imaging across DBS states will advance our understanding of the larger network response to DBS, which is essential to develop more specific stimulation of fibers to improve response and avoid side effects in ET.


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 FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	7/1/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $355,560 )
2024	2024	THE FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	5	7/30/2024	NON-COMPETING CONTINUATION	$355,560
2024	2022	THE FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	12/5/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$510,871
2024	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	12/5/2023	NON-COMPETING CONTINUATION	-$1
2024	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	12/5/2023	NON-COMPETING CONTINUATION	-$450,017
2024	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/5/2023	NEW	-$60,853
														Subtotal = $355,560

Issue Date FY: 2023 ( Subtotal = -$11,514 )
2023	2022	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	9/13/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$438,502
2023	2022	UNIVERSITY OF HEALTH SCIENCE CENTER	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	9/12/2023	NON-COMPETING CONTINUATION	-$450,016
														Subtotal = -$11,514

Issue Date FY: 2022 ( Subtotal = $450,017 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	9/14/2022	NON-COMPETING CONTINUATION	$450,017
														Subtotal = $450,017

Issue Date FY: 2021 ( Subtotal = $450,017 )
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	9/9/2021	NON-COMPETING CONTINUATION	$450,017
														Subtotal = $450,017

Issue Date FY: 2020 ( Subtotal = $395,004 )
2020	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/3/2020	NEW	$395,004
														Subtotal = $395,004

Grand Total All Awards = $1,639,084

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Elucidating the Temporality of Structural and Functional Connectivity Changes in Essential Tremor after successful Deep Brain Stimulation to the dentato-rubrothalamic tract

Award Number: R01NS113893

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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