Public Regulatory Databases as a Source of Insight for Neuromodulation Devices Stimulation Parameters.

OBJECTIVE: The Shannon model is often used to define an expected boundary between non-damaging and damaging modes of electrical neurostimulation. Numerous preclinical studies have been performed by manufacturers of neuromodulation devices using different animal models and a broad range of stimulation parameters while developing devices for clinical use. These studies are mostly absent from peer-reviewed literature, which may lead to this information being overlooked by the scientific community. We aimed to locate summaries of these studies accessible via public regulatory databases and to add them to a body of knowledge available to a broad scientific community. METHODS: We employed web search terms describing device type, intended use, neural target, therapeutic application, company name, and submission number to identify summaries for premarket approval (PMA) devices and 510(k) devices. We filtered these records to a subset of entries that have sufficient technical information relevant to safety of neurostimulation. RESULTS: We identified 13 product codes for 8 types of neuromodulation devices. These led us to devices that have 22 PMAs and 154 510(k)s and six transcripts of public panel meetings. We found one PMA for a brain, peripheral nerve, and spinal cord stimulator and five 510(k) spinal cord stimulators with enough information to plot in Shannon coordinates of charge and charge density per phase. CONCLUSIONS: Analysis of relevant entries from public regulatory databases reveals use of pig, sheep, monkey, dog, and goat animal models with deep brain, peripheral nerve, muscle and spinal cord electrode placement with a variety of stimulation durations (hours to years); frequencies (10-10,000 Hz) and magnitudes (Shannon k from below zero to 4.47). Data from located entries indicate that a feline cortical model that employs acute stimulation might have limitations for assessing tissue damage in diverse anatomical locations, particularly for peripheral nerve and spinal cord simulation.

Electron transfer processes occurring on platinum neural stimulating electrodes: pulsing experiments for cathodic-first/charge-balanced/biphasic pulses for 0.566 ≤ k ≤ 2.3 in oxygenated and deoxygenated sulfuric acid.

The application of a train of cathodic-first/charge-balanced/biphasic pulses applied to a platinum electrode resulted in a positive creep of the anodic phase potential that increases with increasing charge injection but reaches a steady-state value before 1000 pulses have been delivered. The increase follows from the fact that charge going into irreversible reactions occurring during the anodic phase must equal the charge going into irreversible reactions during the cathodic phase for charge-balanced pulses. In an oxygenated electrolyte the drift of the measured positive potential moved into the platinum oxidation region of the i(V e) profile when the charge injection level exceeds k = 1.75. Platinum dissolution may occur in this region and k = 1.75 defines a boundary between damaging and non-damaging levels on the Shannon Plot. In a very low oxygen environment, the positive potential remained below the platinum oxidation region for the highest charge injection values studied, k = 2.3. The results support the hypothesis that platinum dissolution is the defining factor for the Shannon limit, k = 1.75. Numerous instrumentation issues were encountered in the course of making measurements. The solutions to these issues are provided.

Electrical neurostimulation with imbalanced waveform mitigates dissolution of platinum electrodes.

OBJECTIVE: Electrical neurostimulation has traditionally been limited to the use of charge-balanced waveforms. Charge-imbalanced and monophasic waveforms are not used to deliver clinical therapy, because it is believed that these stimulation paradigms may generate noxious electrochemical species that cause tissue damage. APPROACH: In this study, we investigated the dissolution of platinum as one of such irreversible reactions over a range of charge densities up to 160 µC cm-2 with current-controlled first phase, capacitive discharge second phase waveforms of both cathodic-first and anodic-first polarity. We monitored the concentration of platinum in solution under different stimulation delivery conditions including charge-balanced, charge-imbalanced, and monophasic pulses. MAIN RESULTS: We observed that platinum dissolution decreased during charge-imbalanced and monophasic stimulation when compared to charge-balanced waveforms. SIGNIFICANCE: This observation provides an opportunity to re-evaluate the charge-balanced waveform as the primary option for sustainable neural stimulation.

Durability of implanted electrodes and leads in an upper-limb neuroprosthesis.

Implanted neuroprosthetic systems have been successfully used to provide upper-limb function for over 16 years. A critical aspect of these implanted systems is the safety, stability, and-reliability of the stimulating electrodes and leads. These components are (1) the stimulating electrode itself, (2) the electrode lead, and (3) the lead-to-device connector. A failure in any of these components causes the direct loss of the capability to activate a muscle consistently, usually resulting in a decrement in the function provided by the neuroprosthesis. Our results indicate that the electrode, lead, and connector system are extremely durable. We analyzed 238 electrodes that have been implanted as part of an upper-limb neuroprosthesis. Each electrode had been implanted at least 3 years, with a maximum implantation time of over 16 years. Only three electrode-lead failures and one electrode infection occurred, for a survival rate of almost 99 percent. Electrode threshold measurements indicate that the electrode response is stable over time, with no evidence of electrode migration or continual encapsulation in any of the electrodes studied. These results have an impact on the design of implantable neuroprosthetic systems. The electrode-lead component of these systems should no longer be considered a weak technological link.

Design and testing of an advanced implantable neuroprosthesis with myoelectric control.

An implantable stimulator-telemeter (IST-12) was developed for applications in neuroprosthetic restoration of limb function in paralyzed individuals. The IST-12 provides 12 stimulation channels and two myoelectric signal (MES) channels. The MES circuitry includes a two-channel multiplexer, preamplifier, variable gain amplifier/bandpass filter, full-wave rectifier, and bin integrator. Power and control signals are transmitted from an external control unit to the IST-12 through an inductive link. Recorded MES signals are telemetered back to the external control unit through the same inductive link. Following bench testing, one device was implanted chronically in a dog for 15 months and evaluated. Conditions were identified in which MES could be recorded with minimal stimulus artifact. The ability to record MES in the presence of stimulation was verified, confirming the potential of the IST-12 to be used as a myoelectric controlled neuroprosthesis.

A flat interface nerve electrode with integrated multiplexer.

One of the goals of peripheral nerve cuff electrode development is the design of an electrode capable of selectively activating a specific population of axons in a common nerve trunk. Several designs such as the round spiral electrode or the flat interface nerve electrode (FINE) have shown such ability. However, multiple contact electrodes require many leads, making the implantation difficult and potentially damaging to the nerve. Taking advantage of the flat geometry of the FINE, multiplexers were embedded within the cuff electrode to reduce the number of leads needed to control 32 channels. The circuit was implemented on a polyimide film using off-the-shelf electronic components. The electronic module was surface-mounted directly onto the electrode's flat substrate. Two circuit designs were designed, built, and tested: 1) a single supply design with only two wires but limited to cathodic-first pulse and 2) a dual-supply design requiring three lead wires but an arbitrary stimulation waveform. The electrode design includes 32 contacts in a 1 mm x 8 mm opening. The contact size is 300 microm x 400 microm with access resistance less than 1 k ohm. This electrode is not intended for long-term use, but developed as a feasibility study for future development using low-water-absorption materials such as liquid crystal polymer and an application specific integrated circuit.

An implanted myoelectrically-controlled neuroprosthesis for upper extremity function in spinal cord injury.

A second generation implantable neuroprosthesis has been developed which provides improved control of grasp-release, forearm pronation, and elbow extension for individuals with cervical level spinal cord injury. In addition to the capacity to stimulate twelve muscles, the key technological feature of the advanced system is the capability to transmit data out of the body. This allows the use of myoelectric signal recording via implanted electrodes, thus minimizing the required external components. Clinical studies have been initiated with a second generation neuroprosthesis that consists of twelve stimulating electrodes, two myoelectric signal recording electrodes, an implanted stimulator-telemeter device and an external control unit and transmit/receive coil. This system has now been implemented in nine arms in seven C5/C6 spinal cord injured individuals. The results from these subjects demonstrate that myoelectric signals can be recorded from voluntary muscles in the presence of electrical stimulation of nearby muscles. The functional results show that the neuroprosthesis provides significantly increased pinch force and grasp function for each subject. All subjects have demonstrated increased independence and improved function in activities of daily living. We believe that these results indicate that implanted myoelectric control is a desirable option for neuroprostheses.

An advanced neuroprosthesis for restoration of hand and upper arm control using an implantable controller.

An advanced neuroprosthesis that provides control of grasp-release, forearm pronation, and elbow extension to persons with cervical level spinal cord injury is described. The neuroprosthesis includes implanted and external components. The implanted components are a 10-channel stimulator-telemeter, leads and electrodes, and a joint angle transducer; the external components are a control unit and transmitter-receiver coil. The system has completed preclinical testing and has been implanted fully in 3 persons and partially in 1 person, all with tetraplegia caused by spinal cord injury at C5 and C6. The minimum follow-up time for any system component is 16 months. All subjects had improvements in grasp strength, range of motion, and ability to grasp objects and increased independence in activities of daily living. Each subject became a regular user of the neuroprosthesis and is satisfied with it. The implanted components have not caused any medical complications. The operation of the electrodes and sensors has been stable. The data show that this advanced neuroprosthetic system is safe and can provide grasping and reaching ability to individuals with cervical level spinal cord injury.