I. Introduction II. Overview of Challenges and System Requirements

Title: Neurostimulation Design from an Energy and Information Transfer Perspective Authors: David A. Dinsmoor, MSEE,. Wesley A. Santa, BSEE and Larry Tyler, MSEE, Timothy J. Denison, Ph.D (Medtronic Neuromodulation Integrated Circuit Technology)

I.

Introduction

Neurostimulation—defined as electrical charge delivery for the purpose of affecting the behavior of nervous tissue—is arguably one of the fastest growing applications in biomedical engineering. In the United States alone, neurostimulation products represented a $628 million market in 2006 with an expected annual growth rate of 20%.1 Example applications include neurostimulation for pain control, incontinence, hearing loss, epilepsy and essential tremor. Even more exciting for engineers, researchers and venture capitalists are the nascent and under-developed applications of neurostimulation—particularly neurostimulation to restore function lost to neurological diseases or injury. At the heart of any such system is a circuit which drives neural tissue with electricity. This chapter provides provides an overview of the circuit systems required to design a state-of-the-art neurostimulator. Section two outlines a complete system design including all aspects of energy flow, from the battery to the tissue. Section three discusses the details of the tissue-electrode interface design and highlights key safety considerations. The fourth section develops two emerging areas of stimulation that should be considered for future stimulator analysis: closed-loop, adaptive stimulation architectures and optigenetic stimulation. The intent of this chapter is to provide a comprehensive overview, through design tutorials and examples, of how a practical system is architected and implemented.

II.

Overview of Challenges and System Requirements

At the core of any neurostimulation system are the circuits which transfer energy from the charge storage element to the tissue. The role of the implantable neurostimulators (INS) circuit designer is to ensure that the charge delivery circuit (hereinafter the “stimulation engine”) is capable of interacting with all elements of the stimulation system—the target tissue, lead, other elements in the INS and external programmer—so as to meet the goals of safety, efficiency and efficacy. The interface between the stimulating electrode(s) for an INS and the target tissue forms a fairly complex electrochemical interface2 which remains the subject of active research. Paramount to the design of any chronically implanted INS is safe delivery of charge across this interface to the target tissue while still generating the desired physiologic effect. Over the years, researchers have elucidated various electrode designs and stimulation patterns that avoid or limit unintended tissue damage and electrode corrosion during charge delivery.3 Balanced, biphasic charge delivery which does not exceed application dependant stimulation frequency, net DC transfer, charge density and chargePREPRINT DRAFT

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per-phase levels generally results in neurostimulation with limited tissue and electrode damage. These levels for many neurostimulation applications (such as deep brain stimulation, retinal implants and cochlear implants) have been presented in other references and are not discussed further here.4 To this end, most commercially available INS’s (such as the Medtronic Restore™ and St. Jude Medical Eon™) are generally capable of delivering charge in a multi-programmable manner similar to that shown in Figure 1.

Figure 1: Generalized stimulation pulse train. Q(c) is cathodic charge flow out of the tissue; t(c) is the duration of the cathodic charge flow; t(d) is the interval between cathodic and anodic phases; Q(a) is the anodic charge flow into the tissue; t(a) is the duration of the anodic charge flow; F is the frequency of charge delivery. The solid line for Q(a) indicates “active” anodic charge recovery versus the “passive” charge recovery illustrated with the dotted line.5

The key elements of the pulse train shown in Figure 1 are anodic and cathodic charge delivery half-phases, for which the total charge delivered during the anodic phase reverses most—if not all—of the charge delivered in the cathodic phase. The anodic phase may consist of passive or active recharge phases, or a combination thereof. Passive recharge is enabled by the presence of a coupling capacitor which is often placed in series between the INS output and the electrode. One function of this capacitor is to avoid a potential path for DC current flow into the tissue. During passive recharge, charge is allowed to flow into the tissue in a decaying exponential fashion set by the product of the electrode impedance and the coupling capacitor. Passive recharge is the most efficient way to generate the anodic half-phase. During active recharge, charge is actively injected across the electrode-tissue interface for the purpose of rapidly reversing DC potentials on the electrode so as to enhance electrical sensing, limit tissue damage, or allow for balanced-charge high rate stimulation. Only active recharge is possible if coupling capacitors are not used to avoid tissue damage at the electrode / tissue interface. The aforementioned INS design considerations are not new to engineers and scientists. The origins of clinically successful implantable pulse generators (IPG’s) for neurostimulation applications lay in cardiac electrical stimulators which have been in use PREPRINT DRAFT

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clinically since the 1950’s. In the late 1960’s, Medtronic, Inc. began leveraging their cardiac electrical stimulation technology to develop a spinal cord stimulator. Although the fundamental concept of charge delivery to a particular target tissue is similar across cardiac and neurostimulation applications, certain key distinctions do exist for neurostimulators; namely, the need for broader stimulation parameters, more electrodes and capability for rechargeable power sources. These added constraints drive engineers to not only adapt pre-existing technologies, but develop new circuits and design practices as well. Of interest is a comparison of example INS design constraints versus those of cardiac IPG as presented in Table 1. Other general requirements of the system are embodied in this table as well. Very specialized neurostimulation applications such as subretinal stimulators have their own unique set of design requirements.6 Table 1: Example stimulation constraints for an INS versus a cardiac IPG (Medtronic EnPulse DR). For the cardiac IPG, currents are assumed for a 500 ohm load 200 µs after the leading edge of the pace.

Frequency Cathodic / anodic current (peak) Duration of cathodic current Number of electrodes Sensed signal amplitude Battery type Nominal stimulation current Example regulatory standard differences

III.

INS 1 – 250+ Hz 250 µA – 15 mA 30 µs – 2 ms 16 or more > 1 µV, 12-40 Hz (beta band) Secondary or Primary 63 µA (3 mA, 210 µs, 100 Hz) ISO 14708-3 (INS), EN 60118-13 (Cochlear Implant)

Cardiac IPG 0.5 Hz - 3.5 Hz 1 mA – 15 mA 120 µs – 1.5 ms 2 (atrial / ventricular) > 150 µV, 13-30 Hz (atrial depolarization) Primary 5.6 µA (7 mA, 400 µs, 1 Hz), 100% A+V pacing EN 45502-2-1, ISO 14708-2

Completing the Energy Transfer Circuit: From Battery to Body

In many ways, the expanded design constraints and the higher current consumption of the INS over the cardiac IPG cement the stimulation engine as the true heart of the INS—a role typically reserved for the microprocessor in most embedded systems.7 This “stimulation engine-centric” paradigm is presented graphically in Figure 2.

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Figure 2: Signal flow model for neurostimulators illustrating the modes of energy translation from the battery to the tissue 8

The essence of the INS is energy translation as is evidenced in Figure 2. When a battery is used to power the INS electronics—versus direct inductive coupling, a super capacitor, biogalvanic cells or the like—chemical energy is stored in the battery. The redox reactions between the battery electrolyte and the anode / cathode pair result in the battery terminal voltage available to power the rest of the system. In the case of a secondary battery, the electrochemical potential of the battery must be periodically replenished. This is typically accomplished via inductive charging by an external recharger. The stimulation engine in turn utilizes the potential of the battery to drive across the electrochemical phase boundary of the electrode / tissue interface and subsequently modulate the neural activity encoded in the activation patterns of the target nervous tissue. The energy delivered to the tissue can be titrated to meet the unique needs of the particular neurostimulation application, much like certain pharmaceuticals are titrated in a dose-dependent fashion to elicit a specific response. Technological advancements have gradually steered energy titration from physician or patient-mediated “open-loop” control to “closed-loop” control, automatically integrating and feeding back any number of sensed parameters to the stimulation engine for optimal response. With Figure 2 as a reference, we explore a prototype INS where energy flow is traversed starting from the chemical energy stored in the secondary, inductively recharged battery and culminating in charge delivery to the target tissue at the tip of the stimulating electrode. Specific areas of discussion below include recharging and interfacing with the battery, boosting the battery voltage to potentials suitable for therapeutic use, generating PREPRINT DRAFT

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an appropriate stimulation signal, and delivering the stimulation signal to the tissue in a safe and effective manner. We conclude the chapter with a discussion on future directions for neurostimulation circuitry.

III a. Secondary Cell Recharge Secondary cells, when used as the power source for the INS, are typically recharged via an inductively coupled link at low-RF frequencies (10’s of kHz to 10’s of MHz). Other methods such as ultrasonic recharge have been described in the literature9 but have not been used in commercially available devices to-date. The simplest method, as shown in Figure 3, is a standard full-wave rectifier.

Figure 3: Full wave rectifier for secondary cell recharge

In this example, an INS recharger acts as the primary with respect to the secondary coil inside the INS. A current / voltage limiter acts as a variable resistor which prevents the battery from being charged at a higher voltage or charge rate than that allowed by the particular battery chemistry. Unfortunately, the design shown in Figure 3 suffers from the diode drops of D1-D4 which limits its usefulness unless low forward-voltage Schottky diodes are used. Synchronous rectifiers eliminate the diode drops at the expensive of some added complexity; a representative example is shown in Figure 4.

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Figure 4: Synchronous rectifier for secondary cell recharge

As seen in Figure 4, the bridge switches (M1-M4) synchronously open or close in response to the voltages on “Bridge Left” and “Bridge Right.” Switches M1 and M4 close to establish a path for recharge current to flow when node “Bridge Right” flies high. Similarly, when “Bridge Right” is low and “Bridge Left” flies high, switches M2 and M3 are on and conducting. Regardless of the method of rectification used, care must be taken in the following areas: 1. Optimization of inductive link efficiency, 2. Current and voltage management to avoid damage to the INS or interference with other INS elements, and; 3. Thermal management to avoid excessive heating during inductive coupling, either intended or not. The final point above is of special concern because it involves potential risk to the patient should the temperature of the INS rise sufficiently high to cause tissue damage during recharge. Standards such as EN 45502-1: 1997 §17.1 provide guidance on allowable thermal excursions for an INS. The literature is replete with other examples of methods and techniques scientists, engineers and researchers have used to optimally recharge or power their INS’s and other medical devices.10,11 As such, recharge is not discussed further here.

III b. Energy Source Characteristics The characteristics of the INS energy source are critical to the energy flow problem in the INS. As seen in Table 1, secondary cells are frequently used in INS’s versus cardiac IPG’s given the higher overall current draw in the former versus the later. Simply put, primary cells are precluded in high-rate stimulation applications as the higher current draws would necessitate too frequent device change-outs. The discharge curve for an example 3 mA-h Li (Ni, Co, Al)O2 (LNCAO) secondary cell (the Quallion QL0003I) is shown in Figure 5. The “C” annotation on each curve refers to the discharge rate as a function of the nominal battery capacity; for instance, the 2C curve shows the battery discharge curve with a 6 mA load whereas 0.2C indicates a 0.6 mA load. These cells feature a low output impedance (< 10 ohm) to support high-rate charge delivery. This may be contrasted with the much higher impedance (