Using deep brain stimulation (DBS) to target the cerebellar dentate nucleus appears to be a promising approach for treating patients with poststroke motor impairment, with a first-in-human trial showing that the intervention is safe and yields meaningful improvements in motor function when combined with physical therapy.

The EDEN* trial included 12 participants (mean age 57.4 years) with a first-time, unilateral, ischaemic stroke (mean time after index event 2.2 years) that affected the middle cerebral artery territory. Of the participants, four were women and seven had dominant-side paresis. The Upper-Extremity Fugl-Meyer Assessment (FM-UE) score at baseline was 22.9 points. [Nat Med 2023;doi:10.1038/s41591-023-02507-0]

All participants underwent unilateral implantation of a single DBS lead in the contralesional dentate nucleus. After 1 month of recovery from surgery, participants underwent physical rehabilitation twice a week for 2 months without rehabilitation to establish a baseline before activating DBS and to reduce the possibility that any improvements were due to rehabilitation alone.

Then, participants entered the programming phase (4-10 weeks), during which the optimal DBS settings were determined. Once the settings were established, participants entered the DBS plus rehab phase, where DBS was delivered continuously for a minimum of 4 months (maximum of 8 months) while participants continued twice-weekly rehabilitation sessions and an at-home program.

At the end of the DBS plus rehab phase, participants entered the rehab-carryover phase. During this phase, DBS was gradually reduced and then discontinued. Participants continued rehabilitation therapy for an additional month without DBS. If the improvements did not decrease by >50 percent after DBS discontinuation, the DBS hardware was removed surgically.

Safety and feasibility

Data covering 168 participant-months of DBS implant experience and 72 months of dentate nucleus stimulation experience showed that the intervention was safe and feasible.

A total of 51 adverse events, including pain, nausea, tingling and migraine, among others, were documented. There were no reports of device failures and study-related, serious adverse events throughout the trial. Additionally, none of the participants suffered haemorrhages, contracted infections, underwent major perioperative complications, or died.

Transient effects of DBS were noted during the programming phase wherein the stimulation thresholds to side effects were determined, but all stimulation-related effects resolved with reprogramming.

Of the 12 participants, nine had significant reductions in motor impairment and achieved substantial gains in motor function.

“It is noteworthy that these improvements were achieved: (1) in participants with overall poor function at enrolment (mean FM-UE of 22.9 points) and deemed to have poor natural prognosis and (2) after participants underwent a 3-month period of supervised rehabilitation,” according to the investigators led by Drs Andre Machado and Kenneth Baker of Cleveland Clinic, Cleveland, Ohio, US.

However, DBS exerted greater effects for participants who had at least minimal preservation of distal motor function at enrolment, suggesting that severity might play a role in the degree of individual benefit achieved, in line with previous reports. [Neurorehabil Neural Repair 2016;30:107-119; Neurosci Lett 2009;460:152-155]

“We did not observe a correlation between time after stroke and motor improvements associated with DBS plus rehab. As such, participants who were enrolled at 3 years after stroke still demonstrated effects of large magnitude, which counters the expectation that time after stroke might limit treatment-related benefit. These findings are important as they support the potential of DBS to widen the therapeutic window of opportunity for stroke survivors,” Machado and Baker noted.

Dentatothalamocortical pathway activation

By stimulating the cerebellar dentate nucleus, the goal is to increase neural activity in the ipsilesional cortex and improve its excitability through activation of the dentatothalamocortical pathway, which is thought to be involved in different functions, including motor control, sensory processing, and cognitive functions such as attention and working memory. [Front Integr Neurosci 2012;6:20]

Already, earlier studies in animals and humans showed that such an approach is feasible and could potentially help improve motor function and other cognitive functions in people with stroke. [Exp Brain Res 2000;132:314-327; Exp Brain Res 1992;89:352-362; Cerebellum 2005;4:218-223; Cerebellum 2012;11:259-263]

Indeed, “[w]e saw patients in the [EDEN] study regain levels of function and independence they did not have before enrolling in the research. These are reassuring for patients as the participants in the study had been disabled for more than a year and, in some cases, 3 years after stroke. This gives us a potential opportunity for much needed improvements in rehabilitation in the chronic phases of stroke recovery,” according to Machado.

“The quality-of-life implications for study participants who responded to therapy have been significant… This was a smaller study, and we look forward to expanding as we have begun the next phase,” he said.

 

*Electrical Stimulation of the Dentate Nucleus for Upper Extremity Hemiparesis Due to Ischemic Stroke