The associate staff member in the department of neurology at Cleveland Clinic provided perspective on a recently published phase 1 study assessing deep brain stimulation in individuals with chronic poststroke hemiparesis.
Recently published in Nature, a group of experts at Cleveland Clinic conducted a small-scale, phase 1 trial (NCT02835443) assessing the impacts of deep brain stimulation of the dentate nucleus (DN-DBS) on individuals with chronic poststroke hemiparesis. Considered the first of its kind, the trial met its primary end point of safety, with no device failures and no study-related, serious adverse events (AEs) over 168 participant-months of DBS implant experience. Otherwise known as the EDEN trial, 12 patients completed months of physical therapy, first with the DBS device turned off for several weeks and then turned on for 4-8 months.
Following the initial decrease on upper extremity Fugl-Meyer (FM-UE) assessment between the pre- and post-surgery time points, patients showed a modest 3-point (P = .0004) median improvement across the pre-stimulation, 2-month rehab-only phase (no DBS: month 3 vs 1). When rehabilitation was then combined with DN-DBS, patients gained (improved) an additional 7 points (P = .0005). Finally, during the 2-month, rehab-carryover phase, which consisted of continued physical rehabilitation as DBS was weaned (weekly 25% amplitude reductions over the first month) and then OFF (second month), no further change in FM-UE was observed (median change, 0).
In a post-hoc analysis of those with some distal preservation of motor function at baseline (n = 7), this group demonstrated a median gain of 15 points on the FM-UE over the DBS+rehab phase, whereas those with no distal preservation (n = 5) had only a 3-point gain of motor function (P = .007). To learn more about these findings, and the potential of DBS as a rehabilitative method for stroke, NeurologyLive® sat down with Kenneth Baker, PhD, a lead investigator of the study. As part of a new iteration of NeuroVoices, Baker, an associate staff member in the department of neurology at Cleveland Clinic, provided insight on the reasons for targeting the DN, significance of the post-hoc findings, and the next steps in research.
Kenneth Baker, PhD: In considering the best candidate for this approach, I would like to highlight that our learning process is ongoing. This was indeed a key aspect of the initial phase one study—to capture the diverse variations observed within the population. As we progress, we aim to identify features that could guide us in determining the types of patients, specific stroke categories, and the affected brain regions that might significantly influence the potential benefits we can expect. Prior to delving into these details, I want to mention that our groundwork involved thorough preclinical research, as previously suggested. This research originated in the laboratory setting, representing our initial step in transitioning from lab-based investigations to human trials. Our preclinical models enabled us to gauge the likelihood of benefits and understand the contributing factors that might distinguish those who would benefit from those who wouldn't.
Our approach marks something of a paradigm shift in the realm of deep brain stimulation. Typically, deep brain stimulation involves delivering high-frequency pulses based on the assumption that there exists underlying pathophysiology connected to the way the disease presents its symptoms—such as tremors, slow movement, and rigidity. High-frequency stimulation interacts with the system to create an effect that, while the exact mechanisms remain uncertain, could be likened to interrupting the propagation of abnormal neural activity. In our case, we are operating at the lower end of the frequency spectrum for deep brain stimulation. We employ stimulation frequencies around 30 hertz. The rationale here is different; we aim to enhance a specific neural pathway's activity. Essentially, we seek to amplify activity across this pathway to enhance cortical excitability, a crucial factor in the functional reorganization we anticipate. This reorganization will be pivotal as we renew our efforts toward physical rehabilitation in these patients.
The primary message, consistent with the focus in phase 1, centers around safety. Our primary endpoint for this study was indeed safety, given the nature of this open-label study. Ensuring that we could successfully perform the surgical procedure and carry out stimulation, both of which are relatively novel in this specific context, was paramount. Subsequently, we delved into secondary endpoints, which naturally carry our optimism and hopes. In this respect, the most thrilling aspect pertains to the patients' experience. As we embarked on this journey, our familiarity with deep brain stimulation informed us of its risks. However, the key was applying this knowledge to the unique patient population we are addressing. The remarkable part was how, even with modest expectations due to the limited sample size, we were genuinely excited by the outcomes of the initial patient and those that followed. Witnessing our ability to achieve and sometimes exceed the targeted benefits was undoubtedly a high point.
Certainly, this brings us back to the initial question about the population's heterogeneity. Numerous factors contribute to this heterogeneity, spanning imaging results, behavioral patterns, and secondary challenges faced by patients during the chronic phases of the disease—challenges such as spasticity and patterns of learned disuse. In this context, the secondary analyses I mentioned play a vital role in shaping our future steps. They inform our approach for maximizing the risk-benefit balance, a key focus for phase two. As you pointed out, we examined patients based on the extent of their preserved distal extremity function. These patients could be categorized according to a standard scale, which, when coupled with functional evaluations, guided our secondary analysis. Specifically, we observed that patients with a baseline preservation of distal function exhibited notably positive outcomes, aligning with meaningful differences on standard stroke scales.
Phase two is already underway, and it involves a randomized controlled trial. This phase encompasses several aspects, including enrolling around 40 participants. Our emphasis in this phase shifts more towards efficacy. This entails blinded treatment and blinded assessments, all geared towards enhancing the rigor of interpreting the actual efficacy data. We are also expanding the study to include multiple sites across the country, ensuring that the approach's feasibility isn't confined to a single institution but can be applied on a broader scale.
From a fundamental standpoint, this research holds the promise of supporting an overarching approach. It provides hope even in the chronic phase of the disease, where patients typically plateau in terms of performance improvements. The research suggests that there exists a means to modulate cortical function and reorganization, potentially pushing the boundaries of what was previously considered possible. Our unique angle involves chronic stimulation, a key factor that might underlie this effect. Chronic stimulation offers ongoing support to neural circuits, synergizing with patients' rehabilitation efforts. Currently, our pairing approach involves deep brain stimulation and specific neural pathways we've identified as linked to preserved brain areas post-stroke. While our current approach is promising, it's essential to acknowledge that other avenues might prove equally effective or even more so. In this context, ongoing research is crucial as we explore alternative methods and seek ways to enhance the approach's effectiveness. This pursuit of improvement goes hand in hand with our ongoing research efforts.
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