Phase I trial shows promise: Brain stimulation spurs upper-extremity recovery in stroke patients

In a recent article published in Nature Medicine, researchers performed an open-label phase I trial wherein they applied deep brain stimulation (DBS) to the cerebellar dentate nucleus (DN) to promote functional reorganization of the ipsilesional cortex. 

They combined this therapeutic approach with physical rehabilitation to improve post-stroke upper-extremity impairment in 12 individuals who had this condition for one to three years, i.e., persistently.

Study: Cerebellar deep brain stimulation for chronic post-stroke motor rehabilitation: a phase I trial. Image Credit: - Yuri A/Shutterstock.comStudy: Cerebellar deep brain stimulation for chronic post-stroke motor rehabilitation: a phase I trial. Image Credit: - Yuri A/


Post-stroke care costs exceed acute care costs associated with stroke, a leading cause of physical disability worldwide. It is an economic and social burden for individuals having ischemic stroke and their families.

Despite substantial effort and investment, technological leaps for the post-acute phase of stroke have been slower. 

Earlier researchers investigated noninvasive approaches as adjuvant, neurostimulation-based treatments to complement mechanisms governing physical rehabilitation and improve long-term outcomes because most stroke survivors had residual impairment despite receiving contemporary rehabilitation. 

However, the focus has shifted to invasive surgical alternatives, including direct cortical and vagal nerve stimulation (VNS). Contrary to noninvasive therapies, these surgical alternatives provide more demand-based neuro-modulatory effects at home, which is far more convenient. 

In addition, a wide range of treatment approaches for modulating neuroplasticity, i.e., spontaneous/gradual or therapy-driven improvements in motor function after stroke, are currently under exploration in preclinical and clinical trials. 

About the study

In the present study, researchers proposed another novel, invasive surgical approach to extend the temporal window and the extent of neuroplasticity in 12 patients with moderate to severe upper-extremity impairment after stroke. 

This approach involves DN DBS to activate the endogenous dentatothalamocortical pathway and modulate neural activity, including ipsilesional cortical excitability.

The researchers hypothesized that this would promote ipsilesional cortical reorganization and recovery of motor function because this pathway represents a reciprocal loop connecting the cerebral cortex with the stroke-affected contralateral cerebellar hemisphere.

Additionally, they evaluated the safety and feasibility of DBS surgical implantation. Furthermore, they subjected all 12 participants to a suite of secondary assessments to characterize the effect of rehabilitation therapy on upper-extremity motor impairment and function. 

The study participation spanned 20 to 24 months, with monthly assessments performed to record safety data and secondary metrics. Following enrollment, participants underwent one month of upper-extremity rehabilitation to rule out the potential for recovery with rehabilitation therapy. 

Then, each participant underwent DBS surgical implantation, with the lead implanted in the DN contralateral to the cerebral hemisphere. The team performed brain imaging via a T1-weighted volumetric magnetic resonance imaging (MRI) of the head before implantation of the DBS lead.

Later, they used fluorodeoxyglucose (FDG)-positron emission tomography (PET) studies with physical therapy for cerebral metabolic imaging. One month after the surgery, participants resumed twice-weekly physical rehabilitation for two more months.

The rehabilitation protocol comprised repetitive sessions of segmentally graded adaptive task practice based on individual performance.

The ratio of repetitive and adaptive tasks alternated from 1:1 to 1:2 nearly every four weeks to maximize motor function and standardize the rehabilitation dose across all participants. The team actively monitored adverse events, including serious safety events, and unanticipated events, even those due to the surgical device. 


The current trial provided an in-human demonstration of clinically meaningful effects of DN-DBS combined with rehabilitation on post-stroke motor impairment and distal motor function.

At the enrollment, all the participants had no or minimal distal motor function in the upper extremity and corresponding adverse effects on cortical metabolism, as evidenced by a mean improvement of 22.9 points in the Fugl-Meyer-Upper-Extremity (FM-UE).

However, this target population well-tolerated the surgery and chronic stimulation with no study-related serious adverse events throughout the trial. 

Encouragingly, the benefit from this implant was not dependent on time since stroke, with robust improvements observed as late as three years after the first stroke, with a median improvement of 15 UE-FM assessment points. An increased ipsilesional metabolism evidenced that cortical reorganization directly resulted in these robust functional gains.


Token together, the current preliminary findings of this phase I in-human trial confirmed that this new neuromodulation-based surgical and invasive approach was safe, feasible, and promising for modulating the magnitude of neuroplastic reorganization toward recovery of motor function and extending its time window to the late phases of disability after cerebral ischemia (stroke).

Journal reference:
Neha Mathur

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.


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