Motor neuroprosthesis implanted with neurointerventional surgery improves capacity for activities of daily living tasks in severe paralysis: first in-human experience.

BACKGROUND: Implantable brain-computer interfaces (BCIs), functioning as motor neuroprostheses, have the potential to restore voluntary motor impulses to control digital devices and improve functional independence in patients with severe paralysis due to brain, spinal cord, peripheral nerve or muscle dysfunction. However, reports to date have had limited clinical translation. METHODS: Two participants with amyotrophic lateral sclerosis (ALS) underwent implant in a single-arm, open-label, prospective, early feasibility study. Using a minimally invasive neurointervention procedure, a novel endovascular Stentrode BCI was implanted in the superior sagittal sinus adjacent to primary motor cortex. The participants undertook machine-learning-assisted training to use wirelessly transmitted electrocorticography signal associated with attempted movements to control multiple mouse-click actions, including zoom and left-click. Used in combination with an eye-tracker for cursor navigation, participants achieved Windows 10 operating system control to conduct instrumental activities of daily living (IADL) tasks. RESULTS: Unsupervised home use commenced from day 86 onwards for participant 1, and day 71 for participant 2. Participant 1 achieved a typing task average click selection accuracy of 92.63% (100.00%, 87.50%-100.00%) (trial mean (median, Q1-Q3)) at a rate of 13.81 (13.44, 10.96-16.09) correct characters per minute (CCPM) with predictive text disabled. Participant 2 achieved an average click selection accuracy of 93.18% (100.00%, 88.19%-100.00%) at 20.10 (17.73, 12.27-26.50) CCPM. Completion of IADL tasks including text messaging, online shopping and managing finances independently was demonstrated in both participants. CONCLUSION: We describe the first-in-human experience of a minimally invasive, fully implanted, wireless, ambulatory motor neuroprosthesis using an endovascular stent-electrode array to transmit electrocorticography signals from the motor cortex for multiple command control of digital devices in two participants with flaccid upper limb paralysis.

Refinement, Reduction, and Replacement (3R) Strategies in Preclinical Testing of Medical Devices.

The U.S. Food and Drug Administration Center for Devices and Radiological Health (FDA/CDRH) has recently published several in vivo test guidance documents that mention refinements, reductions, or replacement animal testing strategies to facilitate the leveraging of data from large animal safety tests for conventional rodent testing. In response to the recently enacted Food and Drug Administration Safety and Innovation Act Section 907, which facilitates expedited access to novel therapies commonly described as Breakthrough Therapy Designation, FDA/CDRH has discussed efficient regulatory strategies for first-in-human investigation, including early feasibility study guidance. Large gains in humane care and translational research could also be attained by examples in FDA's Guidance for the Use of International Organization for Standardization 10993-1, which states that large animal safety studies may be considered as replacement rodent tests if the scientific principles, methods, and end points (SPME) are considered and applied. This article discusses SPME for the replacement of conventional rodent testing by the inclusion and integration of clinical, diagnostic, and pathologic data obtained from well-designed large animal studies. The recommendations include consideration for study designs that utilize methods for an overall more comprehensive interrogation of animal systems.

Best practices for cardiac magnetic resonance imaging in common large animal research models.

Magnetic resonance imaging has proven to be useful for the study of cardiovascular physiology in health and disease; it provides important data and information about healthy and diseased states in humans and animals, and it facilitates the safe characterization and positioning of medical devices during cardiovascular applications. Looking to the future, magnetic resonance imaging will continue to play a formative role in biomedical research and applications. Here, we discuss how to avoid common pitfalls and provide safe transport, anesthetic support and physiologic support for animals that are used in dedicated or shared cardiovascular imaging facilities.

Altered states part 2: addressing nausea in canine research subjects.

Nausea and emesis can occur for multiple reasons. While research staff can readily empathize with this type of discomfort, proper assessment and treatment can be challenging. In order to provide optimal care for canine research subjects, it is critical that institutions develop a treatment plan and take preemptive measures to control nausea and emesis when they occur.

Altered states part 1: ancillary refinements in managing perioperative distress with canines.

The biomedical research community has made great progress over the last 30 years in improving strategies to detect and manage pain. Managing experimental and procedural anxiety is a more challenging task, and it depends on the continued practice of distinguishing normal and abnormal states of physiology and behavior in animal subjects. Common approaches for managing pain and distress can be optimized by implementing a plan to also monitor and manage anxiety and dysphoria.

Basic research support for shared magnetic resonance imaging resources.

Procedures that enable the collection of longitudinal physiologic and anatomic information can contribute to the reduction and refinement of animal use. Scientists are increasingly turning to noninvasive magnetic resonance imaging (MRI) to obtain such information from animal research subjects. As they make this important investment, research support veterinarians are often tasked with ensuring the proper care and use of laboratory animal research subjects. A basic understanding of MRI equipment, personnel practices, safety, and monitoring of animals and their recoveries is key to implementing a centralized animal MRI facility.

Primate wellness exams.

Non-human primates (NHPs) continue to serve unique animal research needs. Decades of biomedical research have focused on humane restraint and social and environmental enrichment programs necessary to support NHPs, but the housing and care of NHPs remain challenging because of the occupational safety hazards faced by employees who are tasked with the care and use of these valuable animals. Key to obtaining reliable results, providing humane care and ensuring occupational safety when working with NHPs is a sound annual wellness examination. Clinical techniques in veterinary medicine have improved in parallel with efforts to improve psychological well-being, so the timing is opportune to update clinical techniques inside the primate facility.

Refining analgesia strategies using lasers.

Sound programs for the humane care and use of animals within research facilities incorporate experimental refinements such as multimodal approaches for pain management. These approaches can include non-traditional strategies along with more established ones. The use of lasers for pain relief is growing in popularity among companion animal veterinary practitioners and technologists. Therefore, its application in the research sector warrants closer consideration.

Using the facial grimace scale to evaluate rabbit wellness in post-procedural monitoring.

Rabbits are commonly used in biomedical research and might undergo potentially painful procedures during the course of a study. This column discusses the rabbit facial grimace scale as a tool for monitoring post-procedural pain and explains how it can be incorporated into a worksheet for evaluating rabbit wellness.

Optimizing research animal necropsy and histology practices.

Reduction in animal numbers is an important tenet of laboratory animal research. Research animals should undergo complete necropsy at the close of a study to yield valuable information about the effects and safety of experimental manipulations. Proper and thorough tissue collection, storage and assessment are paramount in attaining the most efficient use of animals in research.

Report of the Working Group on Animal Distress in the Laboratory.

Finding ways to minimize pain and distress in research animals is a continuing goal in the laboratory animal research field. Pain and distress, however, are not synonymous, and measures that alleviate one may not affect the other. Here, the authors provide a summary of a meeting held in February 2004 that focused on distress in laboratory animals. They discuss the difficulties associated with defining 'distress,' propose methods to aid in recognizing and alleviating distressful conditions, and provide recommendations for animal research conduct and oversight that would minimize distress experienced by laboratory animals.

Evaluation of efficacy of heartworm preventive products at the FDA.

The Center for Veterinary Medicine, U.S. Food and Drug Administration (FDA/CVM) has authority under the United States Code 21 under Section 514.80 to monitor for adverse experiences of approved animal products. Although veterinarians voluntarily report suspect drug-related events to manufacturers, firms that market FDA-approved animal products must report serious events to the FDA within 15 working days of the veterinarian or pet-owner's call to them. Under the present regulations, canine heartworm preventatives are approved for 100% efficacy after testing in laboratory and field conditions. The report of lack of efficacy against heartworm larvae is a serious adverse drug event because the resulting condition or the treatment of the condition is life threatening. Information on lack of effect that are deemed possibly, probably, or definitely drug-related available for review under generic product on the FDA/CVM website Surveillance of these reports indicates there are some failures for virtually all heartworm prevention product categories. Most failures have been reported in heartworm-endemic states. At this time, it is unclear whether these are representative of the rare occurrences of failure that have been in existence for a long time, but not reported regularly or promptly, or whether there is a true increase in complaints of ineffectiveness and real variability between products. This paper discusses methods, personnel, and procedures in place in the Division of Surveillance that will aid the FDA to better assess heartworm preventive treatment failures. It discusses scoring paradigms presently utilized by FDA/CVM to assess severity of complaints of lack of efficacy against heartworms, and welcomes audience input as to how to improve existing processes. Results suggest that more comprehensive reporting will provide FDA/CVM more accurate surveillance information regarding efficacy problems. Such practices will permit FDA/CVM to better interpret both incidence and severity of in-effect and possible patterns of emerging resistance and to convey this in any necessary updated labeling. It also indicates that as part of that process, practitioners should return to a more conservative testing schedule.