Another First from a Historic Trial: Novel Pairing of Cerebellar DBS with TMS

By Ela Plow, PhD, PT

Cleveland Clinic’s ongoing EDEN trial (Electrical Stimulation of the Dentate Nucleus for Upper Extremity Hemiparesis Due to Ischemic Stroke) is notable for being the first-in-human clinical trial of deep brain stimulation (DBS) for post-stroke rehabilitation.

Yet the investigation (described in detail in this prior post) is charting new territory in another way as well — as the first study to combine the use of cerebellar DBS with transcranial magnetic stimulation (TMS).

The combination is unique because DBS is a surgically implanted “pacemaking” technique, whereas TMS (demonstrated in the photo above) is a nonsurgical technique that modulates brain activity through the delivery of a series of magnetically induced pulses of current. Although pairing these techniques is generally fraught with artifacts, noise, data corruption, etc., our group has achieved success in applying these techniques together in real time.

Lead investigators Andre Machado, MD, PhD, and Kenneth Baker, PhD, have designed the trial to test DBS of the dentatothalamocortical pathways originating from the cerebellum, a site remote from the target area of TMS, which is used to target the motor cortices. My lab’s contribution to the group has been to build filtering strategies to extract valid TMS data during ongoing application of DBS.

Implications may be far-reaching

Thus, while a handful of teams around the world have been successful at pairing DBS with TMS, our group is the first to pair cerebellar DBS with TMS. The implications of accomplishing such a feat are immense, as outlined below.

First, this study design gives us, for the first time, the ability to evaluate mechanisms that have so far been tested only in animals. Preclinical work by Machado, Baker et al has repeatedly demonstrated that cerebellar DBS can facilitate the lesioned motor cortices in the stroke brain. By studying the effect of cerebellar DBS on motor cortical excitability using TMS, we are availing ourselves of the first opportunity to replicate in humans findings witnessed only in animal studies.

Additionally, in a much broader sense, combining cerebellar DBS with TMS opens up many possibilities for the field of neuroscience. One example is the prospect of new insights into the effects of TMS on cerebellar functioning. These effects have remained elusive, in part because cerebellar nuclei are deep and cannot easily be investigated using TMS and also because of the major technical challenges of delivering TMS during functional neuroimaging. Our paradigm, which allows application of TMS to the motor cortices with simultaneous recordings from externalized cerebellar DBS leads, will offer for the first time an opportunity to monitor real-time effects of TMS on the deep cerebellar nuclei.

Finally, in the same vein, combining TMS and DBS can be temporally synchronized so as to maximize opportunities for plasticity. One can envision that timing TMS and DBS pulses in a tight interstimulus synchrony may serve to generate additive effects on residual pathways to the paretic upper limb — effects that exceed those generated separately with each technique.

We look forward to reporting our findings from this unprecedented pairing of TMS with cerebellar DBS in the months and years ahead.

Dr. Plow (shown in the photo at top) is a staff member in Cleveland Clinic Lerner Research Institute’s Department of Biomedical Engineering with an appointment in the Department of Physical Medicine and Rehabilitation.