Background
Stroke is the leading cause of severe disability and the second leading cause of death worldwide. Ischemic stroke—which is the majority of all strokes—is caused by the occlusion of a cerebral artery, typically with a blood clot. The occlusive blood clot causes a critical loss of cerebral blood flow (CBF) to a brain region and thus death of the affected brain tissue. Emergency treatment for ischemic stroke is available in the form of intravenous tissue plasminogen activator (rtPA) and endovascular clot retrieval catheterizations, which either enzymatically dissolve the occlusive blood clot or physically remove it, restoring CBF. But these standard-of-care treatments are rarely used because of the need for specialized personnel and the numerous contraindications to treatment.
Dilation of the cerebral arteries is a well-known effect of facial nerve stimulation that increases CBF and reverses the effects of ischemic stroke in animal models [
1‐
10]. Indeed, one company (BrainsGate) is in late-stage clinical testing of an invasive facial nerve stimulator as a treatment for ischemic stroke in the 8–24 h post-stroke therapeutic window. In contrast, our research team is developing a non-invasive magnetic facial nerve stimulator for clinical use. Our device—called the VitalFlow™ stimulator—places proprietary magnetic stimulation coils on both sides of the head so that the magnetic field is focused upon the geniculate ganglion region of the facial nerve. The axis of the ear canal is oriented at the geniculate ganglion region of the facial nerve, which is the last portion of the nerve to contain the autonomic fibers that at that point separate from the facial nerve trunk as the petrosal projections to the cerebral arteries.
In clinical use at specialized “Stroke Center” hospitals, the VitalFlow stimulator could improve delivery of intravenous rtPA to the site of the occlusive blood clot and allow easier navigation of endovascular catheters to retrieve the occlusive blood clot. The VitalFlow could also provide rtPA- and endovascular catheter-ineligible patients an emergency treatment option. At non-Stroke Center hospitals, VitalFlow treatment would be administered to ischemic stroke patients prior to transport to a Stroke Center for definitive treatment, thereby expanding the availability of stroke healthcare services and reducing the time from stroke onset to an initial brain-saving treatment.
Herein we report the results of translational research with the VitalFlow stimulator. We first describe normal pig experiments that defined the relationship between select stimulation parameters and the CBF response for the purpose of estimating stimulation parameters that can be be used in human testing. We then report the first-in-man test of a clinical prototype VitalFlow stimulator: a study demonstrating the safety, tolerability, and effectiveness of increasing CBF by VitalFlow stimulation in healthy volunteers.
Discussion
Our aim was to refine the parameters for magnetic stimulation of the facial nerve to increase CBF. As previously published [
19], experiments in normal sheep and dog demonstrated CBF increases at a stimulation of 1.5 Tesla power but not at 1.0 Tesla power. Five minutes of stimulation was used in those experiments assuming that it was supramaximal and thus would not fail to induce a CBF response. Here, using the same magnetic stimulation equipment in pigs, we were able to increase CBF with lower stimulation powers and shorter stimulation durations to a degree comparable to what was achieved with higher powers and longer durations of stimulation. Similarly, the pig experiments reported an average CBF increase of 77% over pre-stimulation baseline. Most combinations of stimulation duration and power achieved this level of CBF response in the normal pig, suggesting a steep dose–response curve that rapidly plateaus.
The response to stimulation in our experiments was generally prolonged, lasting 90 min, which is comparable to the effect of magnetic facial nerve stimulation in normal animal and in animals with ischemic stroke [
19,
20]. We also observed that, by applying a second stimulation approximately 100 min after the first one, the elevated CBF could be maintained for at least 3.5 h. After the second stimulation, CBF again rapidly increased, then began decaying at a comparable rate to what occurred after the first stimulation.
The increase in CBF suggests that magnetic stimulation of the facial nerve dilates the cerebral arteries. In our experiments, we examined the angiographic response of the internal carotid artery as representative of the cerebral arteries. We observed dilation of the internal carotid arteries on MR angiography that lasted about 90 min following a single stimulation. The MRI techniques used to measure CBF in these experiments thus showed mutually consistent responses and comparable time courses. We also confirm that unilateral stimulation produces bilateral effects on the cerebral vasculature [
20].
The pig study may have been biased by the involvement of study team in the delivery of the stimulation and the analysis of the outcome data. However, stimulation parameters were allocated in a random fashion and data analysis was performed through automated processes, which should reduce the bias. Other limitations of this study include the testing of restricted stimulation parameters. This is a necessary limitation given the large number of potential combinations of stimulation factors, including not only stimulation power and duration, but other factors such as pulse shape, pulse duration, and stimulation patterns. Clearly all combinations of these parameters cannot be tested in the preclinical setting, and so we focused on those parameters that are most meaningful to the development of a medical device. Reducing stimulation power and duration directly impacts the design of a medical device since they determine the device’s power demands, electronic tolerances, and cooling requirements. What is more, lower stimulation power and duration can only improve a medical device’s safety and tolerability. Thus, it was the intention of this study to determine how little stimulation power and duration could still effectively increase CBF. Indeed, our initial range of stimulation powers and durations proved to be comparably effective at increasing CBF (see Fig.
4), and we had to add-on additional experiments to define the lower end of a dose–response curve (as per Fig.
5).
Our choice of the pig as a translational animal model reflects the general similarities between the pig head anatomy and human head anatomy [
22], which are more closely related than most other, non-primate species. However, the relationship of the pig and human in terms of CBF is less assured, given the connections between the extracranial-intracranial circulation [
23], the presence of a carotid rete in the pig, and the quadruped body positioning of the pig. Yet these limitations are generally shared by most of the large animal models available for this research, and so are unavoidable. While interspecies differences do appear to occur, we do not believe additional preclinical testing needs to be done to extrapolate the current findings about pulsed magnetic facial nerve stimulation (e.g., into primates) before advancing the VitalFlow technology into clinical testing.
The pig study showed that we could reduce VitalFlow stimulation power and duration significantly in comparison with our early animal studies. We also recognized the need for tolerability of VitalFlow stimulation in clinical testing: unlike the pigs and other animal experiments, wherein stimulation was always administered under general anesthesia, clinical use of the VitalFlow would be done in awake people. We realized the need to allow people some control over the stimulation power but also the need to achieve the minimum stimulation necessary to increase CBF. Thus, we decided to rapidly increase the stimulation power with the consent of the volunteer over a period of a minute, with the aim of delivering 2 min of stimulation at a power of at least 1.2 Tesla.
This strategy appeared to be successful: with gentle encouragement, volunteers readily could tolerate VitalFlow stimulation for 2 min at 1.2 Tesla or higher power. At stimulation powers greater than 1.2 Tesla, adverse events were encountered. Overall, the clinical prototype VitalFlow demonstrates a better-than-expected adverse event profile, with few adverse events of interest being reported. Common minor adverse events included jaw pain or soreness, sweating on the neck and face, visual flashes, neck pain or soreness, and nausea. None of these adverse events were limiting of stimulation or posed a serious health risk.
Clear responders to stimulation (i.e., a CBF increase of ≥ 25%) represents about a third of all volunteers, and in that group the response to stimulation could be quite sizable. No clear dose–response relationship could be observed in the available dataset, similar to the pig study. Other studies of facial nerve stimulation have reported inconsistent response to facial nerve stimulation [
24], with some evidence of intra-animal variability in response to repeated stimulation. In part, this may reflect opposing neural reflex mechanisms and/or arterial autoregulation that serve to maintain a steady level of CBF in normal animals. Indeed, in our healthy volunteer study, we unexpectedly observed a high rate of sweating in the head and neck as an adverse event. Sweating reflects activation of the sympathetic nervous system, which may also counteract a CBF response through vasoconstrictive innervation of the cerebral arteries [
25]. Further investigation is needed to understand this intersubject (and potentially intrasubject) variability, and whether or not it occurs in conditions where an increase in CBF is clearly needed by a person, e.g., as in ischemic stroke. We also intend to compare the effectiveness of bilateral versus unilateral stimulation and the ability of repetitive stimulation to maintain elevated CBF in future healthy volunteer studies.
Authors’ contributions
AG, FCP, MP, RLE, OS, MRM, MG, JA, and ES made substnatial contributions to the acquisition of data and the analysis and interpretation of data. AG, FCP, OS, MC, JA, MB, and ES made substantiial contributions to the conception and design of the research. AG, OS, MB, and ES have been involved in drafting and revising the manuscript. All coauthors give their final approval of the manuscript version that will be published, and all coauthors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.