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Establishing the anatomical and functional mechanisms of white matter deep brain stimulation

Award Number: RF1MH132789
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/12/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Establishing the anatomical and functional mechanisms of white matter deep brain stimulation - Project Summary Deep brain stimulation (DBS) targeting white matter instead of specific nuclei or cortex is an emerging therapeutic approach for individuals with treatment resistant neurological or psychiatric disorders. This treatment approach is thought to have its beneficial effects through functional modulation of neural activity across distributed brain networks that connect through the white matter that is being stimulated. Evidence for this is, however, in short supply. This means that the underlying functional and anatomical mechanisms that contribute to the therapeutic effects of white matter DBS are poorly understood. Lack of this knowledge hinders refinement of this treatment and its potential use to target other white matter tracts. Here we will model the effects of DBS in macaques and determine the mechanisms engaged by DBS therapy that targets the location where three white matter tracts – forceps minor, uncinate fascicle and cingulum bundle – overlap in frontal cortex adjacent to subcallosal anterior cingulate cortex (ACC). We will employ this model as prior work has shown that stimulation of these tracts is associated with both fast positive changes in affect as well as slower longer-term effects on affective state that develop over many weeks in people with treatment resistant mood disorders. Our aim here is to establish the micro- and meso-scale neurological changes across both time frames caused by deep brain stimulation. We hypothesize that they are caused by two distinct mechanisms. The fast effects are the result of functional changes whereas the slow changes are the result of structural changes to white matter. To test our hypothesis, we will use a combination of deep brain stimulation, resting-state fMRI, neurophysiology, and postmortem anatomy in macaque monkeys. Using the same diffusion imaging tractography approach used in human patients, mini-deep brain stimulation electrodes will be targeted to the confluence of three white matter tracts. We will then assess the progressive systems level changes in fMRI resting-state functional connectivity and diffusion weighted imaging estimates of anatomical connections that are caused by deep brain stimulation of these three white matter tracts. In parallel, we will assess the microscale neurophysiological changes that occur as a result of stimulation. Here our experiments are designed to discern the immediate effects of stimulation on functional interaction between areas that directly connect through the white matter adjacent to subcallosal ACC as well as the longer-term changes in functional communication between areas. Finally, we will characterize the changes in anatomy that are associated with the brain-wide functional effects of deep brain stimulation to white matter. Here we will use both confocal and electron microscopy to discern alterations to white matter that are caused by stimulation. Completing these experiments will begin to reveal the functional and anatomical mechanisms of DBS when it is directed to white matter. Overall, what we discover will provide insights into how circuit-level functions are modulated by DBS as well as aid the refinement of emerging DBS treatments.


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 = $2,399,556 )
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	3	8/28/2025	EXTENSION WITH OR WITHOUT FUNDS	$2,399,556
														Subtotal = $2,399,556

Grand Total All Awards = $2,399,556

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Establishing the anatomical and functional mechanisms of white matter deep brain stimulation

Award Number: RF1MH132789

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/12/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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