Prospective Home-use Study on Non-invasive Neuromodulation Therapy for Essential Tremor.

Highlights: This prospective study is one of the largest clinical trials in essential tremor to date. Study findings suggest that individualized non-invasive neuromodulation therapy used repeatedly at home over three months results in safe and effective hand tremor reduction and improves quality of life for many essential tremor patients. Background: Two previous randomized, controlled, single-session trials demonstrated efficacy of non-invasive neuromodulation therapy targeting the median and radial nerves for reducing hand tremor. This current study evaluated efficacy and safety of the therapy over three months of repeated home use. Methods: This was a prospective, open-label, post-clearance, single-arm study with 263 patients enrolled across 26 sites. Patients were instructed to use the therapy twice daily for three months. Pre-specified co-primary endpoints were improvements on clinician-rated Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) and patient-rated Bain & Findley Activities of Daily Living (BF-ADL) dominant hand scores. Other endpoints included improvement in the tremor power detected by an accelerometer on the therapeutic device, Clinical and Patient Global Impression scores (CGI-I, PGI-I), and Quality of Life in Essential Tremor (QUEST) survey. Results: 205 patients completed the study. The co-primary endpoints were met (p≪0.0001), with 62% (TETRAS) and 68% (BF-ADL) of \u27severe\u27 or \u27moderate\u27 patients improving to \u27mild\u27 or \u27slight\u27. Clinicians (CGI-I) reported improvement in 68% of patients, 60% (PGI-I) of patients reported improvement, and QUEST improved (p = 0.0019). Wrist-worn accelerometer recordings before and after 21,806 therapy sessions showed that 92% of patients improved, and 54% of patients experienced ≥50% improvement in tremor power. Device-related adverse events (e.g., wrist discomfort, skin irritation, pain) occurred in 18% of patients. No device-related serious adverse events were reported. Discussion: This study suggests that non-invasive neuromodulation therapy used repeatedly at home over three months results in safe and effective hand tremor reduction in many essential tremor patients

Real-World Evidence of Transcutaneous Afferent Patterned Stimulation for Essential Tremor.

Background: Transcutaneous afferent patterned stimulation (TAPS) is a prescription, wrist-worn device-delivered, non-invasive neuromodulation therapy for treatment of hand tremor in patients with essential tremor (ET). This retrospective post-market surveillance study evaluated real-world effectiveness of TAPS from patients using therapy on-demand for at least 90 days between August 2019 through June 2021. Methods: Demographics were summarized from TAPS prescriptions received from the patient\u27s healthcare provider. Therapy usage and effectiveness were analyzed from device logs, which included tremor measurements from onboard motion sensors. Tremor history and patient-reported outcomes were assessed from a voluntary survey. Results: A total of 321 patients (average age 71 years, 32% female) met the criteria for this analysis, 216 of whom had tremor measurements available for analysis and 69 of whom completed the survey. Total usage period ranged from 90 to 663 days, with 28% of patients using the device for over one year. Patients used therapy 5.4 ± 4.5 (mean ± 1 standard deviation) times per week. TAPS reduced tremor power by 71% (geometric mean) across all sessions, with 59% of patients experiencing \u3e50% tremor reduction after their sessions. Eighty-four percent (84%) of patients who returned the voluntary survey reported improvement in at least one of eating, drinking, or writing, and 65% of patients reported improvement in quality of life. Self-reported device-related safety complaints were consistent with adverse events in prior clinical trials. Discussion: Real-world evidence is consistent with prior clinical trials and confirms TAPS provides safe and effective tremor control for many patients with ET. Future work assessing multi-year safety and effectiveness would be valuable to extend these data

Shape-fitting concept.

<p>(A) Automated software was used to identify the target (e.g. putamen). (B) The infusion shape was rastered over each pixel to calculate the geometric intersection (white) of the infusion (gray) and target (gray). (B) Resulting coverage map of the putamen for a single 300 <b>µ</b>L infusion.</p

Retrospective validation of shape-fitting model.

<p>The experimental distribution was measured by the Gadolinium enhancement in the T1-weighted FLASH image of a 250 <b>µ</b>L infusion into the oligodendroglioma tumor of a dog, a 50 <b>µ</b>L infusion into the putamen of a non-human primate, and a 150 <b>µ</b>L infusion into the thalamus of a non-human primate. The color overlays show the target (<i>yellow</i>), infusate (<i>red</i>) and their intersection (<i>white</i>). The target coverage (<i>T</i>) and containment (<i>C</i>) are listed above each overlay. All simulated infusions positioned at the experimentally measured cannula location (middle column) showed strong agreement with the experimental distributions (left column), validating the accuracy of the model spheroid shape. Improving the cannula positioning in the putamen and thalamus would have improved the coverage and containment. The distance between the measured and optimized cannula locations was 0.6 mm in the tumor, 5.07 mm in the putamen and 3.2 mm in the thalamus.</p

Algorithm implementation in a clinical prototype.

<p>User-friendly implementation in software (iPlan®; Brainlab, Munich) which autosegments the target, autosegments the risk structures and identifies the optimal cannula location to maximize coverage and containment.</p

Development of the infusion model.

<p>(A) The length, width and cannula tip location were measured at each timepoint during the infusion (Vi 10 <b>µ</b>L, 50 <b>µ</b>L, 80 <b>µ</b>L, 120 <b>µ</b>L). (B) The width and tip distances scaled linearly with the infusion length. (C) The distance measures scaled as cubic roots (solid lines) of the infusion volume. (D) The resulting spheroid simulation showed good agreement with the measured volumes.</p

Rapid Inverse Planning for Pressure-Driven Drug Infusions in the Brain

Infusing drugs directly into the brain is advantageous to oral or intravenous delivery for large molecules or drugs requiring high local concentrations with low off-target exposure. However, surgeons manually planning the cannula position for drug delivery in the brain face a challenging three-dimensional visualization task. This study presents an intuitive inverse-planning technique to identify the optimal placement that maximizes coverage of the target structure while minimizing the potential for leakage outside the target. The technique was retrospectively validated using intraoperative magnetic resonance imaging of infusions into the striatum of non-human primates and into a tumor in a canine model and applied prospectively to upcoming human clinical trials