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Randomized Controlled Trial
. 2025 May-Jun;18(3):640-648.
doi: 10.1016/j.brs.2025.02.021. Epub 2025 Mar 1.

Acute dentate nucleus deep brain stimulation modulates corticomotor excitability in chronic stroke survivors

Xin Li  1 , Kenneth B Baker  2 , Kyle O'Laughlin  1 , Yin-Liang Lin  3 , Kelsey Baker  4 , Robert Chen  5 , Jacqueline Chen  6 , Andre G Machado  7 , Ela B Plow  8
Affiliations
Randomized Controlled Trial

Acute dentate nucleus deep brain stimulation modulates corticomotor excitability in chronic stroke survivors

Xin Li et al. Brain Stimul. 2025 May-Jun.

Abstract

Background: Deep brain stimulation of the dentate nucleus (DN-DBS) is an emerging therapy to improve upper extremity (UE) motor function after stroke. This study sought to investigate the physiologic mechanisms of acute DN-DBS in chronic stroke survivors enrolled in a phase I trial for DN-DBS.

Methods: Twelve chronic stroke participants with moderate-to-severe UE impairment received (acute) single sessions (≥45 min) of active DBS and sham DBS in a sham-controlled, double-blind, cross-over experiment (order randomized). Transcranial magnetic stimulation (TMS) was used to evaluate corticomotor physiology. We also characterized the relationship between acute DBS effects on physiology and baseline clinical and neuroimaging measures, and chronic DBS effects on motor function.

Results: Acute active DBS led to an increase in ipsilesional corticomotor excitability evident as a 5.2 % maximal stimulator output (MSO) reduction in active motor threshold (p = 0.017, d = 0.28), but there was no effect of acute sham DBS. Increases in corticomotor excitability observed with acute DBS were associated with higher microstructural integrity of ipsilesional corticospinal tract (r > 0.70, p < 0.017) and dentato-thalamo-cortical pathways (ρ > 0.69, p < 0.022). Gains in corticomotor excitability with acute DBS were associated with higher dexterity gains made with chronic DBS plus rehabilitation (r > 0.65, p < 0.028).

Conclusions: Acute DN-DBS leads to heightened ipsilesional corticomotor excitability in moderate-to-severe chronic stroke survivors. Effects of acute DN-DBS on physiology are contingent upon structural preservation of key white matter tracts and associated with motor gains made with chronic DN-DBS. Findings provide mechanistic support of DN-DBS as a potential therapy for post-stroke motor recovery and potential of TMS to monitor responses.

Keywords: Deep brain stimulation; Dentate nucleus; Neurophysiology; Stroke; Transcranial magnetic stimulation; Upper extremity.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Andre Machado reports financial support, administrative support, article publishing charges, equipment, drugs, or supplies, statistical analysis, and travel were provided by National Institutes of Health. Andre Machado reports financial support and equipment, drugs, or supplies were provided by Enspire DBS. Ela Plow reports financial support, administrative support, article publishing charges, equipment, drugs, or supplies, and travel were provided by National Institutes of Health. Ela Plow reports equipment, drugs, or supplies was provided by Enspire DBS. Jacqueline Chen reports financial support was provided by National Institutes of Health. Kelsey Baker reports financial support, administrative support, equipment, drugs, or supplies, and travel were provided by National Institutes of Health. Kenneth Baker reports financial support, administrative support, article publishing charges, equipment, drugs, or supplies, statistical analysis, and travel were provided by National Institutes of Health. Kenneth Baker reports financial support and equipment, drugs, or supplies were provided by Enspire DBS. Kyle O'Laughlin reports financial support, administrative support, and equipment, drugs, or supplies were provided by National Institutes of Health. Kyle O'Laughlin reports equipment, drugs, or supplies was provided by Enspire DBS. Xin Li reports financial support, administrative support, article publishing charges, equipment, drugs, or supplies, statistical analysis, and travel were provided by National Institutes of Health. Xin Li reports equipment, drugs, or supplies was provided by Enspire DBS. Yin-Liang Lin reports financial support, administrative support, and equipment, drugs, or supplies were provided by National Institutes of Health. Yin-Liang Lin reports equipment, drugs, or supplies was provided by Enspire DBS. Andre Machado reports a relationship with Abbott that includes: consulting or advisory. Andre Machado reports a relationship with Novo Nordisk that includes: consulting or advisory. Andre Machado reports a relationship with Enspire DBS that includes: equity or stocks. Ela Plow reports a relationship with National Institutes of Health that includes: funding grants. Ela Plow reports a relationship with American Heart Association that includes: funding grants. Ela Plow reports a relationship with American Society of Neurorehabilitation that includes: board membership. Ela Plow reports a relationship with NINDS StrokeNet that includes: board membership and paid expert testimony. Ela Plow reports a relationship with Cleveland Clinic Rehabilitation Hospital in partnership with Select Medical that includes: board membership, consulting or advisory, and employment. Jacqueline Chen reports a relationship with Biogen that includes: speaking and lecture fees. Kenneth Baker reports a relationship with Enspire DBS that includes: board membership, equity or stocks, and funding grants. Kenneth Baker reports a relationship with Cardionomics, Inc. that includes: equity or stocks. Xin Li reports a relationship with American Heart Association that includes: funding grants. Andre Machado has patent licensed to Enspire DBS. Andre Machado has patent licensed to Ceraxis. Kenneth Baker has patent #Configuring a deep brain stimulation (DBS) system to treat a neurological disorder (USPA: 17/154,045) pending to Cleveland Clinic. Kenneth Baker has patent #System and Process for Closed-Loop Deep Brain Stimulation (USPA: 18/713,215) pending to Cleveland Clinic. Medtronic and Abbott provided support to Cleveland Clinic as fellowship support (Andre Machado). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1.
Fig. 1.
Experimental paradigm.
Fig. 2.
Fig. 2.
A) Bar graphs representing ipsilesional and contralesional AMT values in active and sham DBS conditions across pre-test and post-test timepoints. Light gray lines show individual data. B) Example average MEP traces collected at pre-test and post-test, under active and sham DBS conditions. The intensity used for MEP data collection was the same at both pre-test and post-test. Arrows indicate timing of TMS pulse.
Fig. 3.
Fig. 3.
Bar graphs representing ipsilesional and contralesional MEP values in active and sham DBS conditions across pre-test and post-test timepoints. Light gray lines depict individual data.
Fig. 4.
Fig. 4.
A) Bar graphs representing normalized ipsilesional motor map area (calculated as post/pre ratio) in active and sham DBS conditions. Values < 1 indicate decreased map area from pre-test to post-test; and values > 1 indicate an increase in map area from pre-test to post-test. Dots depict individual data. B) Example ipsilesional motor map contour plots from a participant, where black dots indicate responsive map sites, and white “x” marks indicate non-responsive map sites. Color bar indicate relative size of responses (MEP amplitude normalized to MVC).
Fig. 5.
Fig. 5.
A) Scatterplots showing correlation between longitudinal diffusivity (LD) of the ipsilesional corticospinal tract (CST) and change in corticomotor excitability (AMT) and output (MEP), following active DBS. B) Scatterplots showing correlation between mean diffusivity (MD) of VLp-motor tract and change in corticomotor excitability (AMT) and output (MEP), following active DBS.
Fig. 6.
Fig. 6.
Scatterplots showing correlations between changes in corticomotor excitability (AMT) and output (MEP) following active DBS, and long-term gains in motor dexterity (AMAT quality of movement) following chronic DBS and rehabilitation.
See this image and copyright information in PMC

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