Neural Implants, Electrodes and Electronics Bernie C. Till
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Papers on neural implants, cuff electrodes, electrode arrays, and associated electronics.

Cuff Electrodes - Biocompatibility and Stability

Cuoco Jr., F A, & Durand, D M, 1996: External Pressure Measurements for Nerve Cuff Electrodes, Proc. 18th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 1: 371-372.

When large external pressures are applied to a peripheral nerve, tissue damage can occur via compression and blood flow occlusion, resulting in degeneration and demyelination of axons. This tissue damage must be avoided when implementing nerve cuff electrodes for electrical stimulation of axons. However, post-implant nerve swelling can result in these cuffs exerting large pressures. Currently, only theoretical models are used to predict nerve cuff electrode pressures. The goals of this investigation are (1) to develop a technique to measure external pressures applied by cuff electrodes, (2) to compare experimentally determined cuff pressures with those predicted by theoretical models, and (3) to quantitatively compare different cuff electrodes using a cuff pressure versus nerve diameter relationship. This report describes a pressure measurement technique designed for cuff electrodes and presents some preliminary measurements for various cuff designs.

Cuoco Jr., F A, & Durand, D M, 2000: Measurement of External Pressures Generated by Nerve Cuff Electrodes, IEEE Trans. Rehab. Eng., 8(1):35-41.

When external pressures are applied to a peripheral nerve, tissue damage can occur via compression and blood flow occlusion, resulting in degeneration and demyelination of axons. Although many types of nerve electrodes have been designed to avoid or minimize this pressure during stimulation of the nerve or recording of its activity, the measurement of the pressure exerted by these cuffs has not been reported. Currently, only theoretical models are used to predict nerve cuff electrode pressures. The authors have developed a nerve cuff electrode pressure sensor to measure external pressures exerted by peripheral nerve cuff electrodes. The sensor has a high sensitivity, linear response with little hysteresis and reproducible output. Pressure measurements have been obtained for split-ring and spiral cuff electrodes. The measurements obtained are in agreement with theoretical predictions. Moreover, they indicate that the pressures exerted by cuffs currently used for stimulation generate only a small amount of pressure, which is below the pressure required to occlude blood flow in nerves. The results also suggest that this new sensor can provide reliable measurement of external pressures exerted by nerve electrodes and would be an important tool for comparing various nerve cuff electrode designs.

Grill, W M, & Mortimer, J T, 1998: Stability of the Input-Output Properties of Chronically Implanted Multiple Contact Nerve Cuff Stimulating Electrodes, IEEE Trans. Rehab. Eng., 6(4):364-373.

The objective of this investigation was to measure the input-output (EO) properties of chronically implanted nerve cuff electrodes. Silicone rubber spiral nerve cuff electrodes, containing 12 individual platinum electrode contacts, were implanted on the sciatic nerve of 7 adult cats for 28-34 weeks. Measurements of the torque generated at the ankle joint by electrical stimulation of the sciatic nerve were made every 1-2 weeks for the first 6 weeks post-implant and every 3-5 weeks between 6 weeks and 32 weeks post-implant. In 3 implants the percutaneous lead cable was irreparably damaged by the animal within 4 weeks after implant and further testing was not possible. One additional lead cable was irreparably damaged by the animal at 17 weeks post-implant. The 3 remaining implants functioned for 28, 31, and 32 weeks. Input-output curves of ankle joint torque as a function of stimulus current amplitude were repeatable within an experimental session, but there were changes in EO curves between sessions. The degree of variability in I-O properties differed between implants and between different contacts within the same implant. After 8 weeks, the session to session changes in the stimulus amplitude required to generate 50% of the maximum torque (150) were smaller (15±19%, mean ±s.d.) than the changes in 150 measured between 1 week and 8 weeks post-implant (34±42%). Furthermore, the I-O properties were more stable across changes in limb position in the late post-implant period than in acutely implanted cuff electrodes. These results suggest that tissue encapsulation acted to stabilize chronically implanted cuff electrodes. Electrode movement relative to the nerve, de- and regeneration of nerve fibers, and the inability to precisely reproduce limb position in the measurement apparatus all may have contributed to the variability in I-O properties.

Grill, W M, & Mortimer, J T, 1995: Temporal Stability of Nerve Cuff Electrode Recruitment Properties, IEEE Eng. in Med. & Biol. Soc. 17th Annual Conf., 2:1089-1090.

The recruitment properties of multiple contact nerve cuff electrodes chronically implanted on the cat sciatic nerve were measured, and the week to week variability was documented. The variability in recruitment properties was greatest between 1 week and 8 weeks post-implant. After 8 weeks the session to session changes were significantly smaller than in the early post-implant period. No trends were observed in the recruitment patterns that would suggest any damage to the nerve occurring during the implant period. These results suggest that the implant is safe and that tissue encapsulation acts to stabilize the cuff electrode and prevent relative movement between the cuff and the nerve trunk. This study, combined with previous studies, demonstrates that multiple contact spiral nerve cuff electrodes can be used in long-term implants to activate discrete regions of peripheral nerve trunks.

Polasek, K H, Hoyen, H A, Keith, M W, Kirsch, R F, & Tyler, D J, 2005: Intraoperative Testing of Selectivity of Spiral Nerve Cuff Electrodes, Proc. 2nd Int'l IEEE EMBS Conf. Neur. Eng., 486-489.

Nerve cuff electrodes were used intraoperatively to stimulate peripheral nerves to test electrode selectivity in the human upper extremity. Subjects were recruited from patients undergoing upper extremity nerve repair procedures. The nerves were stimulated through different contacts in the cuff and with varying parameters. Data was recorded to estimate stimulation threshold and determine selectivity data. Thresholds appeared to be higher than anticipated based on previous cat data. Preliminary selectivity was demonstrated on several nerves.

Polasek, K H, Hoyen, H A, Kirsch, R F, & Tyler, D J, 2004: Intraoperative Testing of Selectivity of Spiral Nerve Cuff Electrodes, Proc. 26th Annual Int'l Conf. Eng. in Med. & Biol. Soc., 2:4137-4140.

Nerve cuff electrodes were used intraoperatively to stimulate peripheral nerves to test electrode selectivity in the human upper extremity. Subjects were recruited from patients undergoing upper extremity nerve repair procedures. The nerves were stimulated through different contacts in the cuff and with varying parameters. Estimates of threshold and selectivity data were recorded. The stimulation thresholds found were an order of magnitude higher than prior animal studies using the spiral nerve cuff electrode. Preliminary selectivity was found on the ulnar nerve and the upper trunk of the brachial plexus of one subject. The biceps and pectoralis major were selectively activated by a single cuff placed proximally, on the upper trunk; the flexor carpi ulnaris and first dorsal interosseous were selectively activated by a single cuff placed on the ulnar nerve.

Cuff Electrodes - Design and Fabrication

Andreasen, L N S, & Struijk, J J, 2003: Artefact Reduction with Alternative Cuff Configurations, IEEE Trans. Biomed. Eng., 50(10):1160-1166.

In nerve cuff electrode recordings of neural signals, the pick-up of interfering signals can be reduced by choosing appropriate cuff configurations. In the traditionally used tripolar configuration, short circuiting of the end electrodes is expected to reduce the field inside the cuff from interfering signals. A model study suggests that moving the end electrodes toward the center of the cuff reduces the pick-up of interfering signals . In this paper, these properties are studied in more detail using a rabbit model. In addition, a new cuff configuration is suggested, which has an additional set of short circuited end electrodes. The total improvement of signal-to-noise ratio in the new configuration as compared with the traditionally used tripolar configuration was 73% for muscle signals and 127% for the stimulus pulse.

Andreasen, L N S, & Struijk, J J, 2002: Signal Strength Versus Cuff Length in Nerve Cuff Electrode Recordings, IEEE Trans. Biomed. Eng., 49(9):1045-1050.

When a nerve cuff electrode is used for the recording of signals from peripheral nerves, cuff dimensions have to be chosen. Traditionally, the peak-to-peak amplitude of the single-fiber action potential (SFAP) is optimized through the choice of cuff diameter and cuff length. In this paper, the dependency of the root-mean-square (RMS) value of the nerve signal on the cuff dimensions was studied and compared with the peak-to-peak value of the SFAP. A simple approximation for signal optimization by cuff dimensioning is suggested. The results were obtained from modeled SFAPs and from the electroneurogram (ENG) created by superimposed SFAPs, obtained from an inhomogeneous volume conductor model. The results show that the RMS value of the nerve signal is considerably more sensitive to the cuff length than the SFAP peak-to- peak amplitude, and that the RMS of the ENG is a linear function of the fiber diameter.

Andreasen, L N S, & Struijk, J J, 2001: Signal Strength in Nerve Cuff Electrode Recordings, Proc. 23rd Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 1:719-720.

The Nerve Cuff Electrode has been widely to record nerve signals. The correct choice of cuff dimensions and configurations has shown to be crucial for optimization of the signal to noise ratio in the recordings. Traditionally the peak-peak amplitude of the single fiber action potential is optimized through the choice of cuff dimensions. In this work the dependency of the root mean square value (RMS) of the nerve signal on the cuff dimensions was studied. This was done by superpositioning single fiber action potentials obtained from an inhomogeneous volume conductor model. The results showed that the RMS value of the nerve signal was considerably more sensitive to the cuff length than was the peak-peak amplitude.

Andreasen, L N S, & Struijk, J J, 1998: On the Importance of Configuration and Closure of Nerve Cuff Electrodes for Recording, Proc. 20th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 6:3004-3007.

The extraction of neural information for feedback in functional electrical stimulation is limited by the poor signal to noise ratio (SNR) in the nerve recordings. Cuff electrodes have been successful in improving the SNR, but many parameters such as cuff dimensions, configurations and closing methods affect the obtainable SNR. In the present work we studied the effect of the monopolar and tripolar configuration on signal and noise in cuff recordings. Further, we compared two different cuff closures, the slit closure and the closure using interdigitating tubes. The cuff recordings were performed with an artificial nerve fiber set-up, and the results showed that the tripolar configuration gave a 2.4 times higher SNR than the monopolar configuration. A slit closure with a flap resulted in a 6% reduction of the nerve signal amplitude whereas the closure using interdigitating tubes reduced the signal with 19%.

Andreasen, L N S, Struijk, J J, & Haugland, M, 1997: An Artificial Nerve Fiber for Evaluation of Nerve Cuff Electrodes, Proc. 19th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 5:1997-1999.

The different applications of natural sensors for feedback in rehabilitation systems using functional electrical stimulation (FES) require specialised and optimised designs of nerve cuff electrodes for recording of the sensory information. This paper describes a simple artificial nerve fiber for evaluation of nerve cuff electrode designs, cuff recording configurations and noise reduction methods in a controlled environment. The idea is to experimentally identify the transfer function from a nerve fiber to the cuff electrode and make a computed construction of a single fiber action potential. This is done using an action current template as input to the identified transfer functions. The artificial nerve was tested on three cuffs of different lengths and the results showed good agreement with the results from a nerve conduction model of a single fiber action potential in an inhomogeneous volume conductor.

Caparso, A V, & Durand, D M, 2002: A Nerve Cuff Electrode for Controlled Reshaping of Neural Geometry, Proc. Second Joint EMBS/BMES Conf., 3:2054-2055.

The purpose of this study is the development of a silicone nerve cuff electrode that reshapes nerve geometry slowly and controllably. Previous work using a reshaping electrode called the Flat Interface Nerve Electrode (FINE) has shown that the FINE has the ability to reshape the nerve and fascicles into elongated ovals. Reshaping the geometry too quickly may cause neural insult. The Slowly Closing Flat Interface Nerve Electrode (SC-FINE) is designed to control the reshaping period and alleviate any potential nerve compression injury. This is done by combining the reshaping properties of the FINE and the controllable degradation of a biodegradable polymer. Poly (DL lactic-co-glycolic) acid (PLGA) is applied to both sides of a stretched FINE to increase the opening height and control the time period of reshaping. Twenty eight SC-FINEs were manufactured. Their opening heights were measured and the average was 1.72 mm ± 0.47 mm. Preliminary in-vitro experiments to test the reshaping period were performed using 75/25 lactic to glycolic copolymer. Three SC-FINEs, with no delamination of the PLGA film, returned to the original geometry within 15 days ± 8 hours.

Cavanaugh, J K, Lin, J-C, & Durand, D M, 1996: Finite Element Analysis of Electrical Nerve Stimulation, Proc. 18th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 1:355-356.

A nerve stimulation model and tool have been developed to analyze and optimize the design of nerve cuff electrodes. A finite element method was used to determine the electric potentials in the volume conductor. Nerve fiber excitation was determined using the net driving function algorithm. Extraneural and interfascicular cuff electrode configurations were modeled. Selectivity indexes were calculated on various cuff configurations to analyze the effectiveness of selectively activating a given fascicle. The authors' results show that interfascicular cuffs have higher selectivity than extraneural cuffs due to isolation created by the cuff itself.

Chintalacharuvu, R R, Ksienski, D A, & Mortimer, J T, 1991: A Numerical Analysis of the Electric Field Generated by a Nerve Cuff Electrode, Proc. 13th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 912-913.

We have developed a three dimensional finite element model of an unifasicular nerve and the effects of tissue conductivities in and around the nerve trunk on the potential distribution due to a cuff electrode. From the potential distribution we can estimate the region of the nerve trunk where fibers of specific diameter are excited. Our results indicate that selective activation of the nerve fibers was affected by the anisotropy of the nerve trunk and the perineurium. Tripolar configuration, with a smaller spacing between the anodes and the cathode, was more effective in confining the current to the superficial regions or the nerve trunk relative to a monoplar configuration and selectivity of excitation was further improved by steering the current with an anode located across the cathode.

Choi, A Q, Cavanaugh, J K, & Durand, D M, 2001: Selectivity of Multiple-Contact Nerve Cuff Electrodes: A Simulation Analysis, IEEE Trans. Biomed. Eng., 48(2):165-172.

Advances in functional neuromuscular stimulation (FNS) have increased the need for nerve cuff designs that can control multiple motor functions through selective stimulation of selected populations of axons. This selectivity has proved to be difficult to achieve. Recent experiments suggest that it is possible to slowly reshape peripheral nerve without affecting its physiological function. Using computer simulations the authors have tested the hypothesis that changing the cross section of a nerve from a round to a flat configuration can significantly improve the selectivity of a nerve cuff. The authors' introduce a new index to estimate selectivity to evaluate the various designs. This index is based on the ability of a nerve electrode to stimulate a target axon without stimulating any other axons. The calculations involve a three-dimensional finite element model to represent the electrical properties of the nerve and cuff and the determination of the firing properties of individual axons. The selectivity rating was found to be significantly higher for the Flat Cuff than the Round Cuff. The result was valid with uniform or random distribution of axons and with a random distribution of fascicles diameters. Flattening of individual fascicles also improved the selectivity of the Flat Cuff but only when the number of contacts used was increased to maintain uniform contact density. Therefore, cuff designs that can reshape the nerve into flatter configurations should yield better cuff performance than the cylindrical cuffs but will require higher contact density.

Crampon, M-A, Sawan, M, Brailovski, V, & Trochu, F, 1998: New Nerve Cuff Electrode Based on a Shape Memory Alloy Armature, Proc. 20th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 5:2556-2559.

The authors present a new nerve cuff electrode based on a shape memory alloy (SMA) armature. This device is dedicated to functional electrical stimulation of the bladder in spinal cord injured patients. The SMA armature performs the closing of the electrode, making its instillation around the nerve much easier, quicker and safer. Both remarkable mechanical properties of SMA materials namely shape memory effect and superelasticity, can be used to obtain the desired actuation of the electrode closing. The manufacturing procedure of this new electrode is described. It does not require any expensive or complex techniques. Bipolar and tripolar electrodes have been manufactured with an inner diameter of 1.6 mm and a cuff wall thickness of 0.8 mm. Acute studies in dogs are being carried out to validate the device and the implantation procedure. In order to test the electrical functionality of the electrode, a fully programmable biphasic stimuli generator has been designed and implemented using FPDs (Field Programmable Devices).

Durand, D M, Yoo, P, & Lertmanorat, Z, 2004: Neural Interfacing with the Peripheral Nervous System, Proc. 26th Annual Int'l Conf. Eng. in Med. & Biol. Soc., 2:5329-5332.

Although electrical stimulation has proven to be capable of restoring neuronal function in the damaged or injured nervous system, there are several limitations to this technique. The availability of electrodes capable of selective fascicle recruitment and physiological fiber diameter recruitment (from small to large) is crucial for the development of successful prostheses. Nerve cuff electrodes have several advantages over other methods since they can provide activation of multiple muscles groups from a single site. Current cuff electrodes are reshaping the nerve into round shapes and making it difficult to recruit selectively fibers in the center of the nerve. Yet two major problems have not yet found satisfactory solutions: 1) fascicle selectivity and fiber diameter selectivity. We present here a new design that reshapes the nerve into a flat configuration, the flat interface nerve electrode (FINE). This design can improve the ability of the electrode to selectively activate the various fascicles of the nerve. Experiments to measure this selectivity were carried out on the hypoglossal nerve and its three main branches. The ability to recruit various fascicles was estimated using a selectivity index (SI). The overall performance of the FINE, as defined by the selectivity index (SI), showed a high degree of selectivity at both the fascicular and muscular levels: 0.91 ± 0.05 (n = 5) and 0.85 ± 0.03 (n = 4), respectively. This flat interface design minimizes the maximum distance between each contact and the fibers. Computer simulation have shown that it is possible to reverse the recruitment order by using electrode arrays placed along the nerve. This model prediction was tested in the lateral gastrocnemius/soleus branch of the sciatic nerve in cats since these muscles are innervated by fibers with different diameters. A stimulus electrode was placed around LG nerve. Tendons of LG and soleus muscles were separated and attached to two independent force transducers. The recruitment curves generated by tripolar and array electrodes were compared. Tripolar stimulation recruited LG before soleus muscles as expected, whereas the electrode array fully activated soleus while activating only 50% of LG muscles. These results show that the electrode array is capable of reversing the recruitment order by manipulating the extracellular voltage along the nerve.

Fenik, V, Fenik, P, & Kubin, L, 2001: A Simple Cuff Electrode for Nerve Recording and Stimulation in Acute Experiments on Small Animals, J. Neuroscience Methods, 106(2):147-151.

We describe a cuff-type electrode specifically designed for recording from, and electrical stimulation of, cut nerves in acute experiments on small animals. Unlike existing designs of cuff electrodes, it is simple to manufacture, inexpensive and takes little time to implant. The electrode was tested on the hypoglossal, phrenic, recurrent laryngeal, and superior laryngeal nerves in anesthetized rats. It provides satisfactory signal-to- noise ratios (3.0±0.8 (mean±S.D.)) for hypoglossal and 5.4±2.1 for phrenic nerve activity and stable recording over the time course of a typical acute experiment. It eliminates or minimizes the problems with recording stability and space availability associated with conventional hook-type electrodes, and reduces experiment preparation time. This should facilitate neurophysiological experiments on small rodents involving complex protocols that include recording from, and/or stimulation of, multiple nerves.

Goodall, E V, de Breij, J F, & Holsheimer, J, 1996: Position-Selective Activation of Peripheral Nerve Fibers with a Cuff Electrode, IEEE Trans. Biomed. Eng., 43(8):851-856.

The degree of spatial selectivity which can be obtained with longitudinal dot tripoles in an insulating cuff was quantified in terms of the overlap between fiber populations activated by different tripoles. Previous studies have failed to take into account the relative influences of transverse current and longitudinal current on position-selective activation, and furthermore have not controlled for the differing sensitivities of large and small nerve fibers to electrical stimuli. In this study, these factors were taken into account. Transverse current from an anode positioned opposite the stimulating cathode was found to improve spatial selectivity, and selectivity was enhanced when the ratio of transverse current to longitudinal current was increased. Large fibers were excited before small fibers, irrespective of fiber position, indicating a combination of position and size selectivity.

Grill, W M, & Mortimer, J T, 1996: Quantification of Recruitment Properties of Multiple Contact Cuff Electrodes, IEEE Trans. Rehab. Eng., 4(2):49-62.

Nerve-based stimulating electrodes provide the technology for advancing the function of motor system neural prostheses. The goal of this work was to measure and quantify the recruitment properties of a 12 contact spiral nerve cuff electrode. The cuff was implanted on the cat sciatic nerve trunk, which consists of at least four distinct motor fascicles, and the torque generated at the ankle joint by selective stimulation of the nerve was recorded in nine acute experiments. Comparisons of torques generated with the cuff to torques generated by selective stimulation of individual nerve branches indicated that the cuff allowed selective activation of individual nerve fascicles. Selectivity was dependent on the relative location of the electrode contacts and the nerve fascicles, as well as the size and relative spacing of neighboring fascicles. Selective stimulation of individual nerve fascicles allowed independent and graded control of dorsiflexion and plantarflexion torques in all nine experiments. Field steering currents improved selectivity as reflected by significant increases in the maximum torques that could be generated before spillover to other fascicles, significant increases in the difference between the current amplitude at spillover and the current amplitude at threshold, and significant increases in the slope of the current distance relationship.

Grill, W M, & Mortimer, J T, 1993: Functional Control of Joint Torque with a Cuff Electrode, Proc. 15th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 1328-1329.

Three acute experiments were conducted on adult cats to test the performance of a multiple contact nerve cuff electrode in the control of joint torque. A cuff implanted on the sciatic nerve allowed selective and progressive control of the magnitude and direction of the isometric torque about the ankle joint. Use of transverse field steering current improved the selectivity of torque control and increased the dynamic range of torque production. The results suggest that the multiple contact nerve cuff will be a useful component of future motor prosthesis systems.

Hansen, M, Haugland, M K, & Sinkjaer, T, 2004: Evaluating Robustness of Gait Event Detection Based on Machine Learning and Natural Sensors, IEEE Trans. Neur. Sys. & Rehab. Eng., 12(1):81-88.

A real-time system for deriving timing control for functional electrical stimulation for foot-drop correction, using peripheral nerve activity as a sensor input, was tested for reliability to investigate the potential for clinical use. The system, which was previously reported on, was tested on a hemiplegic subject instrumented with a recording cuff electrode on the Sural nerve, and a stimulation cuff electrode on the Peroneal cuff. Implanted devices enabled recording and stimulation through telelinks. An input domain was derived from the recorded electroneurogram and fed to a detection algorithm based on an adaptive logic network for controlling the stimulation timing. The reliability was tested by letting the subject wear different foot wear and walk on different surfaces than when the training data was recorded. The detection system was also evaluated several months after training. The detection system proved able to successfully detect when walking with different footwear on varying surfaces up to 374 days after training, and thereby showed great potential for being clinically useful.

Haugland, M, 1996: A Flexible Method for Fabrication of Nerve Cuff Electrodes, Proc. 18th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 1:359-360.

A method for construction of cuff electrodes is presented. The method is based on using platinum foil electrodes fixed by rubber bands on a Teflon coated mandrel, that is then dip-coated with silicone. The method allows for design of cuff electrodes of practically any size, shape and electrode configuration, and simple cuffs can be built in less than one hour of work. Cuff electrodes have been built that range in size from 0.5 to 10 mm ID and 5 to 70 mm length and number of electrodes from one to twelve. Tri-polar recording electrodes have been tested in more than 30 chronic implantations in rabbits (tibial nerve) and for various acute experiments, where different electrode configurations were investigated. None of the chronic implants have failed and impedances have been stable for one year.

Hoekema, R, Venner, K, Struijk, J J, & Holsheimer, J, 1998: Multigrid Solution of the Potential Field in Modeling Electrical Nerve Stimulation, Computers & Biomed. Res., 31(5):348-362.

In this paper, multilevel techniques are introduced as a fast numerical method to compute 3-D potential field in nerve stimulation configurations. It is shown that with these techniques the computing time is reduced significantly compared to conventional methods. Consequently, these techniques greatly enhance the possibilities for parameter studies and electrode design. Following a general description of the model of nerve stimulation configurations, the basic principles of multilevel solvers for the numerical solution of partial differential equations are briefly summarized. Subsequently, some essential elements for successful application are discussed. Finally, results are presented for the potential field in a nerve bundle induced by tripolar stimulation with a cuff electrode surrounding part of the nerve.

Lin, C C K, Ju, M S, Soung, B H, & Tseng, C T, 2003: Designing and Fabricating Micro-Pressure Sensors for Spiral Cuff Electrodes, Proc. First Int'l IEEE EMBS Conf. Neur. Eng., 197-199.

The cuff electrode, an important component of neural prostheses has been developed and improved in many research groups. It is well known that the cuff electrode has the potential hazard of causing nerve injury by compression. The goal of the study is to design a spiral cuff electrode with an embedded micro-pressure sensor by using micro- electro-mechanical system (MEMS) technologies. The pressure sensors serving as an online well-being monitor, can prevent schemic necrosis of a nerve from excessive pressure. We adopted a capacitive mechanism as the basic configuration because of its high sensitivity and good noise resistance. The sensor was designed and simulated with finite element analyses.

McNeal, M, , D R, Baker, L L, & Symons, J T, 1989: Recruitment Data for Nerve Cuff Electrodes: Implications for Design of Implantable Stimulators, IEEE Trans. Biomed. Eng., 36(3):301-308.

Recruitment characteristics of nerve cuff electrodes, implanted in four cats for five months, were measured. Monopolar, bipolar, and tripolar configurations were considered. Approximately twice the current was required to achieve a given response using the tripolar configuration as compared with monopolar stimulation. Bipolar stimulation also required more current than did monopolar stimulation. A number of strategies for modulating muscle tension were considered using the recruitment data. It was shown that both pulse amplitude and pulse duration should be software-selectable to achieve adequate control of muscle tension when using either pulse-amplitude modulation or pulse-duration modulation. The effects of pulse-amplitude and pulse- duration step size on the maximum step change in muscle tension and the linearity of the recruitment curves were examined. The use of logarithmic steps in the modulation parameter was examined and shown to result in improved controllability and linearity.

Malachowski, K, Albert, M, & Bartha, J-W, 2003: Novel Thin Film Cuff Electrode for Neural Stimulation, 26th Int'l Spring Seminar on Electronics Technology, 13-17.

One approach to reestablish disabled functions or to treat chronic diseases of patients is the electrical stimulation of nerves. This requires, in addition to special stimulator electronics, a dedicated electrode in close contact with the specific nerve. We present a new type of spiral self suing nerve cuff electrode capable of selective activating specific regions of a nerve trunk. The cuff consists of eight active contacts produced by technologies taken from microelectronics. A platinum metalization for contacts and connection wires was made on a sandwich flexible bi-layer polyimide foil substrate embedded in a biocompatible insulation (silicone). With such a design wrap thickness under 40 µm were obtained. The spiral-like arrangement of the cuff placed around the nerve hunk allows a tight cuff-to-nerve contact without penetrating the nerve. The miniaturized active contact area along with the increased number of electrodes imply a highly spatial selectivity together with the need far a high charge transfer. Therefore we are focusing our research on alternative coatings like iridium oxide which promises to enable high current densities. The electrode's design, requirements and production are described.

Mitsui, M, Takeuchi, S, Suzuki, T, Ohkura, M, & Mabuchi, K, 2003: Flexible Intra-Fascicular Nerve Electrodes for the Recordings of Autonomous Nerves, Proc. First Int'l IEEE EMBS Conf. Neur. Eng., 67-70.

We propose a flexible intra-fascicular nerve electrode for control of an artificial heart fabricated by micro machining techniques. We have studied methods for the control of an artificial heart by using autonomous nerve information. Though several approaches have been reported for chronic measurements from peripheral nerves, stable and long- term measurements from autonomous nerves have not yet been established. In order to realize stable and low-invasive measurements, we focused on the electrode's flexibility. Our electrode is fabricated on a flexible polyimide film using micro machining techniques. The electrode consists of four needle-shaped flexible probes. After the planar patterning process, the tips of each probe are bent perpendicularly for insertion into the nerve bundle. The recording sites are placed on the tips of the each probe for the purpose of contacting nondamaged nerve areas. Also the hook-shaped structures are fabricated near the tips to avoid tips and nerve bundle shifting. As a result of preliminary experiments, the thickness of the film that is able to be inserted into the vagal nerve bundle of goat is 75 µm. As a first step for the evaluation for the electrodes, we were able to successfully measure neural activities of the sciatic nerve bundle of rats.

Mortimer, T, Agnew, W F, Horch, K, Citron, P, Creasey, G, & Kantor, C, 1995: Perspectives on New Electrode Technology for Stimulating Peripheral Nerves with Implantable Motor Prostheses, IEEE Trans. Rehab. Eng., 3(2):145-154.

The limits of present electrode technology are being reached in current motor prostheses for restoring functional movement in paralyzed people. Improved devices require electrodes and stimulation methods that will activate muscles selectively and independently with less implanted hardware. A practical functional neuromuscular stimulation (FNS) system may need to employ extraneural, intraneural, epimysial, or intramuscular electrodes or a combination of these types. The limitations of current muscle electrodes and the anatomy of peripheral nerve innervation of muscle have pointed to stimulation of peripheral nerve trunks as a promising area for investigation. Attempts to use conventional (extraneural) peripheral nerve electrodes for selective activation of muscles in chronic applications have met with only limited success. Intraneural (intrafascicular) electrodes offer the advantages of greater selectivity and lower power requirements, but these may be offset by the difficulty of inserting delicate electrodes through the collagenous epineurium and perineurium while avoiding unacceptable amounts of trauma. Cuff electrodes require more power than intrafascicular ones but may provide more stable recruitment patterns over time, and the opportunity for retrieval and replacement.

Naples, G G, Mortimer, J T, Scheiner, A, & Sweeney, J D, 1988: A Spiral Nerve Cuff Electrode for Peripheral Nerve Stimulation, IEEE Trans. Biomed. Eng., 35(11):905-916.

A novel type of nerve cuff electrode consisting of conductive segments embedded within a self-curling sheath of biocompatible insulation has been developed. This spiral nerve cuff is biased to self-wrap around peripheral nerves and possesses a 'self-sizing' property, presenting an alternative to present commercially available, fixed-size nerve cuffs that are manually wrapped around nerves and sutured shut ('split-cylinder' cuffs). Spiral cuff design and manufacture are described. The authors hypothesize that unlike traditional cuffs, the spiral cuff potentially can be implanted safely when sized to fit peripheral nerves snugly. Theoretical pressure analyzes of traditional and spiral cuffs that support this hypothesis are presented. These analyses are designed to predict the minimum CNR (cuff diameter/nerve diameter ratio) at which there is no interference with intraneural blood flow. Results of a preliminary experiment in which snug spiral cuffs were implanted on feline peripheral nerve support the prediction that they may be safe.

Perez-Orive, J, & Durund, D M, 2000: Modeling Study of Peripheral Nerve Recording Selectivity, IEEE Trans. Rehab. Eng., 8(3):320-329.

Recording of sensory information from afferent fibers can be used as feedback for the closed-loop control of neural prostheses. Clinical applications suggest that recording selectively from various nerve fascicles is important. Current nerve cuff electrodes are generally circular in shape and use a tripolar recording configuration. Preliminary experiments suggest that slowly changing the shape of the nerve to a flatter cross section can improve its selectivity. The objective of this work is to determine the effects of nerve reshaping and other cuff design parameters on the fascicular recording selectivity of a nerve cuff. A finite-element computer model of a multifasciculated nerve with different cuff electrodes was implemented to simulate the recordings. The model included the inhomogeneous and anisotropic properties of peripheral nerves. The recording selectivity was quantified with the use of a Selectivity Index. The results from the model provided information regarding the effect of using monopolar versus tripolar recording configurations, the length of the tripoles in tripolar recordings, the number of contacts that maximize the selectivity index, and the cuff length. Nerve reshaping was found to cause important recording selectivity improvements (106% average). These results provide specific criteria for the design of selectively recording nerve cuff electrodes.

Racz, G B, & Heavner, J E, 1989: Comments, with Reply, on 'A Spiral Nerve Cuff Electrode for Peripheral Nerve Stimulation' by G.G. Naples Et Al, IEEE Trans. Biomed. Eng., 36(11):1140-1141.

The commenters, on the basis of the history of cuff electrodes, express the opinion that the use of the cuff electrode for peripheral nerve stimulation described by G.G. Naples et al. (ibid., vol.35, no.11, p.905-16, 1988) has little future. In a reply, the authors of the original paper vigorously dispute this assertion.

Sahin, M, & Durand, D M, 1999: Signal-To-Noise Ratio of Nerve Signals Recorded with Full and Open Cylinder Cuff Electrodes, Proc. First Joint BMES/EMBS Conf., 1: 485.

The authors compared the signal-to-noise ratios (SNRs) of nerve recordings obtained with an open cuff (a 270° cylinder) and a full cylindrical electrode (simulated by lifting the open electrode outside the solution) using an in vitro set-up. The thermal noise was considered as the main source of noise. The SNR with the open cuff was only 52±7% (n=3) less than that of a full cylindrical electrode, although the reduction in signal amplitude was 3.5±0.6 times. One may prefer to use the open cuff geometry to reduce the risk of nerve insult in certain nerve recording applications where this loss in SNR is acceptable.

Sahin, M, & Durand, D, 1997: An Interface for Nerve Recording and Stimulation with Cuff Electrodes, Proc. 19th Annual Int'l Conf. IEEE Eng. in Med. & Biol. society, 5:2004-2005.

A nerve cuff electrode interface capable of both stimulating and recording from a nerve is described. The interface also rejects the EMG contamination in the recordings using reactive components without adding noise to the ENG signal. A transformer is added to the design for noise matching and the signal-to-noise ratio improvement is evaluated for a specific amplifier (AMP-O1).

Sahin, M, & Durand, D M, 1996: Selective Recording with a Multi-Contact Nerve Cuff Electrode, Proc. 18th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 1:369-370.

A multi-contact cylindrical nerve cuff electrode was evaluated for its ability to record neural signals selectively in an in vitro preparation, Three branches of a Beagle hypoglossal nerve are stimulated sequentially while compound action potentials (CAP) are recorded from its trunk with the multi-contact cuff electrode. A selectivity index (SI) is defined and applied to the CAP recorded from the 4 sets of tripolar contacts (12 contacts in total) that are equally spaced around the cuff. The results show that the cuff can record selectively from different fascicles, but these effects are small. Connecting the contacts of the opposite set together while recording from a tripole improved the selectivity. The signal amplitudes from various contacts are consistent with the location of the fascicles relative to the contacts.

Sahin, M, Durand, D M, & Haxhiu, M A, 1994: Whole Nerve Recordings with the Spiral Nerve Cuff Electrode, Proc. 16th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc.,1:372-373.

The feasibility of whole nerve recordings from the hypoglossal (HG) nerve is demonstrated in acute cats using the spiral nerve cuff electrode. A good contact between the nerve and the electrodes, provided by the spiral nerve cuff due to its self- coiling property, should improve the signal-to-noise ratio. An instrumentation amplifier with very low input noise characteristics is also utilized. The performance of the spiral cuff is studied in terms of signal-to-noise ratios and frequency characteristics. We conclude that the spiral nerve cuff electrode can reliably be used for acute recordings in a laboratory environment.

Schuettler, M, Stieglitz, T, Gross, M, Altpeter, D, Staiger, A, Doerge, T, & Katzenberg, F, 2001: Reducing Stiffness and Electrical Losses of High Channel Hybrid Nerve Cuff Electrodes, Proc. 23rd Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 1:769-772.

For restoration of grasp in disabled people by means of functional electrical stimulation of peripheral nerves, 18 polar Hybrid Cuff Electrodes were developed. These electrodes consisted of a micromachined polyimide-based thin-film structure with integrated electrode contacts and interconnection lines which was glued to a silicone cuff. Interconnection lines were made of only 300 nm of sputtered gold, which led to high line drops. Cold electroplating was used to thicken the lines to 3 µm, which reduced the mean track resistance from 480 W to 10 W. Furthermore, the electrode material was changed from sputtered platinum to electroplated platinum black in order to decrease the phase border impedance of stimulation sites. Applying these techniques, the overall electrode impedance could be reduced from 7.78 kW to 624 W (at 1 kHz). Additional to the electrical optimization of the cuff electrodes, mechanical properties were enhanced by changing the method of joining silicone and polyimide from using one part silicone adhesive to plasma activation of surfaces: Plasma-treated surfaces were simply pressed face to face. The result was a bondage without any additional layer of glue, which led to a very high mechanical flexibility and higher yield of the overall Hybrid Cuff Electrode.

Schuettler, M, Koch, K P, Stieglitz, T, Scholz, O, Haberer, W, Keller, R, & Meyer, J-U, 2000: Multichannel Neural Cuff Electrodes with Integrated Multiplexer Circuit, Proc. 1st Annual Int'l Conf. Microtechnologies in Med. & Biol., 624-629.

In order to restore hand function in spinal cord injured people by functional electrical stimulation of arm nerves, the authors developed an 18-polar neural cuff type electrode with integrated multiplexer circuit. This circuit reduces the number of necessary interconnection leads to a stimulator from twelve to four. Cable reduction was intended to reduce the risk of cable breakage which is one of the main reasons for implant failure. The multiplexer cuff electrode was fabricated applying a combination of micromachining, hybrid integration and traditional silicone technology, which enabled one to make the system robust, mechanically flexible and small in size.

Schuettler, M, Stieglitz, T, & Meyer, J-U, 1999: A Multipolar Precision Hybrid Cuff Electrode for FES on Large Peripheral Nerves, Proc. First Joint BMES/EMBS Conf., 1:383.

There are two different techniques that can be applied for fabricating a nerve cuff electrode: 1. traditionally used silicon rubber tubes or spirals and 2. micromechanical methods. Each technique has its own advantages and restrictions. A hybrid cuff combines desired properties of both: high flexibility, high possible numbers of integrated electrodes, high reproducibility and the ability to embrace nerves even with large diameters.

Stieglitz, T, Schuettler, M, Schneider, A, Valderrama, E, & Navarro, X, 2003: Noninvasive Measurement of Torque Development in the Rat Foot: Measurement Setup and Results From Stimulation of the Sciatic Nerve with Polyimide-Based Cuff Electrodes, IEEE Trans. Neur. Sys. & Rehab. Eng., 11(4):427-437.

In neural rehabilitation, selective activation of muscles after electrical stimulation is mandatory for control of paralyzed limbs. For an evaluation of electrode selectivity, a setup to noninvasively measure the force development after electrical stimulation in the rat foot was developed. The setup was designed in accordance to the anatomical features of the rat model to test the isometric torque development at given ankle positions in an intact leg. In this paper, the setup design and development is presented and discussed. In a first study, the selectivity of small nerve cuffs with 12 electrodes implanted around the rat sciatic nerve was investigated. Special attention was drawn to the performance of the torque measurement setup in comparison to electrophysiological data obtained from compound muscle action potential recordings. Using one cuff around the nerve, electrical stimulation on different electrode tripoles led to plantarflexion and dorsiflexion of the foot without an a priori alignment of the cuff.

Stieglitz, T, Schuettler, M, & Meyer, J-U, 1999: Micromachined Multichannel Cuff Electrodes for Interfacing Small Nerves, Proc. First Joint BMES/EMBS Conf., 1:487.

Cuff electrodes are often used for interfacing nerves. Especially for small nerves, a new approach of flexible and light-weighted multichannel cuff electrodes with integrated cables has been developed using micromachining technologies. Here, the process technology is shortly introduced. The results of in vitro test were discussed. In vivo implantations showed excellent properties of the electrode nerve interface.

Struijk, J J, Thomsen, M, Larsen, J O, & Sinkjaer, T, 1999: Cuff Electrodes for Long-Term Recording of Natural Sensory Information, IEEE Eng. in Med. & Biol. Magazine, 18(3):91-98.

Cuff electrodes for recording of the electro-neurogram from peripheral nerves were introduced by Hoffer [1974] and Stein, et al. [1975]. The cuffs were used to obtain higher signal amplitudes than previously possible, at least in chronic recordings, and to decrease the pick-up of noise, especially from muscles. Cuff electrodes are relatively stable in long-term recordings, but the stability has never been quantified in terms of input-output relationships; i.e., in terms of responses to repeatable stimuli over time. Moreover. The relationship between nerve damage and electrophysiological parameters has never been assessed. In this article, after reviewing the development of cuff electrodes and their applications, we present a long-term study of tactile peripheral nerve signals, electrically activated nerve signals, and impedance measurements. We show how the recordings vary over a 16-month period after implantation of nerve cuff electrodes in rabbits, and how nerve damage is reflected in the recorded signals.

Struijk, J J, Haugland, M K, & Thomsen, M, 1996: Fascicle Selective Recording with a Nerve Cuff Electrode, Proc. 18th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 1:361-362.

A multipolar split cuff electrode is used for fascicle selective recording of the electroneurogram (ENG) of the sciatic nerve of the rabbit. Several electrode configurations were evaluated with regarding to selectivity: the peroneal and tibial nerves were stimulated alternately and the ENG was recorded at different sides of the sciatic nerve. The results for two electrode configurations are presented.

Struijk, J J, & Thomsen, M, 1995: Tripolar Nerve Cuff Recording: Stimulus Artifact, EMG and the Recorded Nerve Signal, IEEE 17th Annual Conf. Eng. in Med. & Biol. Soc., 2:1105-1106.

Properties of nerve cuff recording electrodes were analyzed. Tripolar cuff electrodes have to be described essentially different for (propagating) nerve signals inside the cuff, and electrical muscle activity and stimulus artifacts arising from sources outside the cuff. It was experimentally shown that the signals originating outside the cuff are differently and much stronger influenced by the addition of a balancing resister to the outer cuff electrodes than the nerve signal.

Tarler, M D, & Mortimer, J T, 2004: Selective and Independent Activation of Four Motor Fascicles Using a Four Contact Nerve-Cuff Electrode, IEEE Trans. Neur. Sys. & Rehab. Eng., 12(2):251-257.

Any one of the four motor nerves in the cat sciatic nerve could be activated selectively and independently, from threshold to saturation, using a self-sizing spiral cuff electrode containing four radially placed monopolar contacts. These studies were carried out in nine adult cats with acute implants. Of the 36 possible fascicles, 23 fascicles could be activated selectively with current stimuli applied to a single contact and ten of the remaining fascicles could be activated selectively with current stimuli applied to two contacts, "field steering." In three experiments, time constraints precluded attempting selective activation through "field steering" techniques. In eight of the ten cases where "field steering" was used, a positive and a negative current source (anodic steering) were required to achieve the desired fascicle and in the remaining two cases, two negative current sources (cathodic steering) were required. The relative distance from the electrode contacts to each fascicle was well correlated to the order in which each fascicle was activated. In seven experiments, carried out in two animals, selective activation was verified by collision block techniques. The results of these experiments support the hypothesis that selective and independent activation of any of four motor fascicles in the cat sciatic nerve is possible using a four contact self-sizing spiral cuff electrode. Furthermore, in a more general case, these results support the concept of a "tunable" electrode that is capable of "steering" the excitation from an undesirable location to a preferred location.

Tarler, M D, & Mortimer, J T, 2003: Comparison of Joint Torque Evoked with Monopolar and Tripolar Cuff Electrodes, IEEE Trans. Neur. Sys. & Rehab. Eng. 11(3):227-235.

Using a self-sizing spiral-cuff electrode placed on the sciatic nerve of the cat, the joint torque evoked with stimulation applied to contacts in a monopolar configuration was judged to be the same as the torque evoked by stimulation applied to contacts in a tripolar configuration. Experiments were carried out in six acute cat preparations. In each experiment, a 12-contact electrode was placed on the sciatic nerve and used to effect both the monopolar and tripolar electrode configurations. The ankle torque produced by electrically evoked isometric muscle contraction was measured in three dimensions: plantar flexion, internal rotation, and inversion. Based on the recorded ankle torque, qualitative and quantitative comparisons were performed to determine if any significant difference existed in the pattern or order in which motor nerve fibers were recruited. No significant difference was found at a 98% confidence interval in either the recruitment properties or the repeatability of the monopolar and tripolar configurations. Further, isolated activation of single fascicles within the sciatic nerve was observed. Once nerve fibers in a fascicle were activated, recruitment of that fascicle was modulated over the full range before "spill-over" excitation occurred in neighboring fascicles. These results indicate that a four contact, monopolar nerve-cuff electrode is a viable substitute for a 12 contact, tripolar nerve-cuff electrode. The results of this study are also consistent with the hypothesis that multicontact self-sizing spiral-cuff electrodes can be used in motor prostheses to provide selective control of many muscles. These findings should also apply to other neuroprostheses employing- cuff electrodes on nerve trunks.

Tarler, M D, & Mortimer, J T, 1997: Quantification of Similarities in Recruitment Properties of Monopolar and Tripolar Configurations, Proc. 19th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 5:2000-2001.

Nerve cuff electrodes have been shown to be safe and capable of effecting selective and controlled activation of select segments of a peripheral nerve. This selectivity has been shown using a cuff with four equally spaced tripole electrodes employing twelve contacts and twelve lead wires. With present technology, constructing a twelve contact, twelve lead wire nerve cuff is not feasible for safe chronic implementation in a human. In the study presented here, the authors evaluate the monopolar configuration for its simplified and reduced number of contacts and lead wires. Based on the similarity of current flow patterns between monopolar and tripolar configurations, the recruitment characteristics should be similar. Both the overlap between monopolar and tripolar configurations and the repeatability of each configuration was measured. A statistical difference was not found between monopolar and tripolar configurations nor was a statistical difference found for the repeatability of each configuration. Based on these findings the authors conclude that a four contact monopolar cuff electrode can be used in place of a twelve contact tripolar cuff electrode.

Tarler, H, Grill, W M, & Mortimer, J T, 1995: Comparison Between Monopolar and Tripolar Configurations in Chronically Implanted Nerve Cuff Electrodes, IEEE 17th Annual Conf. Eng. in Med. & Biol. Soc., 2:1093-1094.

Nerve cuff electrodes have been shown to be safe and able to activate selectively specific fascicles in a nerve trunk. Selectivity has been shown using a cuff with four radially placed tripoles thus requiring twelve contacts and twelve lead wires. This study evaluates a simplified cuff electrode, consisting of four radially placed monopole electrodes, requiring only four lead wires, and compares the results to the tripolar electrode configuration. Experiments were performed on two cats, each with an electrode that was implanted for over six months. Results from a correlation analysis and a torque vector likeness measure indicated that the recruitment characteristics of the two configurations were similar in 6 of 8 cases.

Tyler, D J, & Durand, D M, 1997: A Slowly Penetrating Interfascicular Nerve Electrode for Selective Activation of Peripheral Nerves, IEEE Trans. Rehab. Eng., 5(1):51-61.

To meet the future needs of functional electrical stimulation (FES) applications, peripheral nerve electrodes must be able to safely, selectively, and independently stimulate small subpopulations of the axons within a common nerve trunk. A new electrode has been designed to place contacts outside of the perineurium, but within the epineurium of the nerve. This slowly penetrating interfascicular nerve electrode (SPINE) combines the safety and simplicity of extraneural cuff electrodes with the intimate interface of intrafascicular wire and probe electrodes. The authors briefly discuss a mathematical method of quantifing performance of nerve electrodes based on the functional output of the intact neuromuscular system. The quantification involves three variables: (1) the functional recruitment trajectory (FRT), (2) functional overlap (O), and (3) overall functional selectivity (?). Second, the authors present results from six acute SPINE implants on the feline sciatic nerve. Quantification of stimulation results demonstrate interfascicular stimulation is functionally different than extraneural stimulation in 32 of 38 trials. In 19 of 28 trials, interfascicular stimulation is functionally selective based on depth of penetration and 52 of 58 trials demonstrate selectivity based on the side of the penetrating element. Third, tissue sections show that the SPINE electrode penetrates into the nerve within 24 h without evidence of edema or damage to the perineurium.

Yoo, P B, & Durand, D M, 2005: Selective Recording of the Canine Hypoglossal Nerve Using a Multicontact Flat Interface Nerve Electrode, IEEE Trans. Biomed. Eng., 52(8):1461-1469.

A flat-interface nerve electrode (FINE) is presented as a potential solution for using multifascicle nerve recordings as part of a closed-loop control system. To investigate the ability of this electrode to achieve selective recordings at physiological signal-to- noise ratio (SNR), a finite-element model (FEM) of a beagle hypoglossal nerve with an implanted FINE was constructed. Action potentials (AP) were generated at various SNR levels and the performance of the electrode was assessed with a selectivity index (0 £ SI £ 1); ability of the electrode to distinguish two active sources). Computer simulations yielded a selective range (0.05 £ SI £ 0.76) that was 1) related to the interfiber distance and 2) used to predict the minimum interfiber distance (0.23 mm £ d £ 1.42 mm) for selective recording at each SNR. The SI was further evaluated using recorded compound APs elicited from electrically activating the branches of the beagle hypoglossal nerve. For all experiments (n=7), the selectivity (SI=0.45±0.16) was within the range predicted by the FEM. This study suggests that the FINE can record the activity from a multifasciculated nerve and, more importantly, distinguish neural signals from pairs of fascicles at physiologic SNR.

Yoo, P B, & Durand, D M, 2003: Selective Fascicular Recording of the Hypoglossal Nerve Using a Multi-Contact Nerve Cuff Electrode, Proc. 25th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 3:2172-2175.

The use of nerve cuff electrodes as part of a closed loop functional electrical stimulation (FES) system has been demonstrated as a reliable alternative to artificial sensors (e.g., strain gauge). To circumvent the need for multiple electrodes to record neural activity from different fascicles within a nerve, the flat interface nerve electrode (FINE) is presented as a potential approach to discern spatially disparate sources using a single implantable device. The recording selectivity of the FINE was investigated using both experimental and computational methods. This involved analyzing recorded action potentials from six acute beagle experiments and a finite element model, which was constructed from a nerve image obtained from one experiment. The performance of the electrode was assessed by a selectivity index that quantified the recording selectivity at the fascicle level. The computed overall selectivity of the FINE was SI_FINE = 44.5 ± 11.2 and SI_FINE = 52.2 for the experimental (n = 7) and computational (n = 1) data, respectively. The results of this study indicate the feasibility of using the FINE as a means of selectively recording neural signals from a multifasciculated nerve.

Yoo, P B, & Durand, D M, 2001: Selective Stimulation of the Hypoglossal Nerve with a Multi-Contact Cuff Electrode, Proc. 23rd Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 2:1309-1312.

The feasibility of selectively stimulating the hypoglossal nerve (XII) with a multi-contact flat-interface-nerve-electrode (FINE) was investigated for the potential application of treating obstructive steep apnea (OSA). The main trunk of the XII was stimulated with monophasic cathodic pulses, while the elicited electroneurographic (ENG) and electromyographic (EMG) signals were recorded. Selective fascicular stimulation of the XII was achieved but with certain limitations: branches 1 and 2 could not be independently activated and the ranges of stimulus current associated with selective stimulation were small. Nevertheless, in terms of independently activating the protrudor and retractor muscle groups that are relevant to OSA, the ENG data suggests that sufficient control of pharyngeal airway patency can be achieved with this method. The functional selectivity of the FINE, however, was more difficult to address in these experiments. Selective activation of individual muscle groups was not possible but that of the retractor muscle group itself was observed. The results of this paper raise the issue of how fascicles are recruited when whole nerves are stimulated with multi- contact cuff electrodes. In order to answer this question, modification of the FINE may be warranted.

Cuff Electrodes - Signal Acquisition

Demosthenous, A, & Triantis, I F, 2005: An Adaptive ENG Amplifier for Tripolar Cuff Electrodes, IEEE J. Solid-State Circuits, 40(2):412-421.

Electroneurogram (ENG) recording from tripolar cuff electrodes is affected by interference signals, mostly generated by muscles nearby. Interference reduction may be achieved by suitably designed amplifiers such as the true-tripole and quasi-tripole systems. However, in practice their performance is severely degraded by cuff imbalance, resulting in very low output signal-to-interference ratios. Although some improvement may be offered by post filtering, this considerably increases complexity, size and power dissipation, rendering the approach unsuitable for the development of a high-performance ENG recording system which is fully implantable. This paper describes an integrated, fully implantable, adaptive ENG amplifier developed to automatically compensate for cuff imbalance, and thus significantly improve the quality of the recorded ENG. Measured results show that the adaptive ENG amplifier has a yield of 100%, a cuff imbalance correction range of more than ±40%, and an output signal-to-interference ratio of about 2/1 (6 dB) even for ±40% imbalance. The latter should be compared with an input signal-to-interference ratio of 1/500 (-54 dB). The circuit was fabricated in 0.8-µm BiCMOS technology, has a core area of 0.68 mm/sup 2/, and dissipates 7.2 mW from ±2.5 V power supplies. The adaptive ENG amplifier advances the state-of-the-art in implantable tripolar nerve cuff electrode recording techniques.

Demosthenous, A, Taylor, J, Triantis, I F, Rieger, R, & Donaldson, N, 2004: Design of an Adaptive Interference Reduction System for Nerve-Cuff Electrode Recording, IEEE Trans. Circuits & Sys. I, 51(4):629-639.

This paper describes the design of an adaptive control system for recording neural signals from tripolar cuff electrodes. The control system is based on an adaptive version of the true-tripole amplifier configuration and was developed to compensate for possible errors in the cuff electrode balance by continuously adjusting the gains of the two differential amplifiers. Thus, in the presence of cuff imbalance, the output signal-to- interference ratio is expected to be significantly increased, in turn reducing the requirement for post-filtering to reasonable levels and resulting in a system which is fully implantable. A realization in 0.8-µm CMOS technology is described and simulated and preliminary measured results are presented. Gain control is achieved by means of current-mode feedback and many of the system blocks operate in the current- mode domain. The chip has a core area of 0.4 mm/sup 2/ and dissipates 3 mW from ± 2.5V power supplies. Measurements indicate that the adaptive control system is expected to be capable of compensating for up to ±5% errors in the tripolar cuff electrode balance.

Goodall, E V, Kosterman, L M, Holsheimer, J, & Struijk, J J, 1995: Modeling Study of Activation and Propagation Delays During Stimulation of Peripheral Nerve Fibers with a Tripolar Cuff Electrode, IEEE Trans. Rehab. Eng., 3(3):272-282.

Computer simulations were performed to investigate the timing of action potential production and propagation in nerve fibers ranging in diameter from 5 to 15 µm during stimulation with a tripolar cuff electrode. The influence of stimulus pulse amplitude and duration on size selective excitation and blocking was considered. Because the stimulus duration required to produce anodal blocking depends on the time at which the action potential arrives at the blocking anode, delays in fiber activation and action potential propagation were investigated. They were found to be dependent on fiber diameter as well as stimulus amplitude and duration. The total delay associated with events occurring at the cuff electrode could be expressed as the sum of the activation delay and the propagation delay. Simple exponential equations were proposed for calculating activation and propagation delay as functions of fiber diameter and stimulus amplitude. Estimates of delays in action potential production and propagation may be useful for the design of electrodes and selection of stimuli for producing selective blocking of nerve fibers, and also for the analysis of compound neural signals elicited by electrical stimulation.

Haugland, M K, & Hoffer, J A, 1994: Artifact-Free Sensory Nerve Signals Obtained From Cuff Electrodes During Functional Electrical Stimulation of Nearby Muscles, IEEE Trans. Rehab. Eng., 2(1):37-40.

Restoration of the voluntary use of paralyzed limbs using functional neuromuscular stimulation (FNS) is limited by complex muscle properties and unpredictable load behaviors; closed-loop control of FNS would improve performance but requires reliable sensory feedback modalities. Sensory nerve signals recorded by cuff electrodes provide accurate information about forces acting on the skin in anesthetized animals; however, nerve cuff signals are very small (approximately 10 µV), and during FNS they become contaminated with large stimulation artifacts and synchronous EMG potentials from nearby muscles. The authors show in this study that it is possible to record neural signals from the cat tibial nerve without interference from distributed stimulation of four calf muscles surrounding the recording electrode by use of high-pass filtering and synchronized bin-integration. Nerve signals sampled in this way retained all the information about footpad contact force that was normally obtained in the absence of muscle stimulation. The authors propose that this approach has wide applicability for rehabilitation of paralyzed people with neural prostheses.

Papathanasiou, K, & Ehmann, T L, 2000: An Implantable CMOS Signal Conditioning System for Recording Nerve Signals with Cuff Electrodes, Proc. IEEE Int'l Symp. Circuits & Sys., 5:281-284.

We propose a system architecture for recording nerve signals with cuff electrodes and develop the key component in this system, the small-input, low-noise, low-power, high- gain amplifier. The amplifier is implemented using a mixture of weak- and strong- inversion transistors and a special off-set compensation technique; its performance is validated using Spice simulations.

Rahal, M, Winter, J, Taylor, J, & Donaldson, N, 1999: Interference Reduction in Nerve Cuff Electrode Recordings-A New Approach, Proc. 1999 IEEE Int'l Symp. Circuits & Sys., 6:493-496.

A method is presented to reduce the interference pickup in nerve cuff recordings. The gains of differential amplifiers connected to the true tripole nerve cuff arrangement are tuned adaptively to null the residual EMG. Simulation results show that extraction of the neural signal is possible using this method without the need for high order filtering.

Rahal, M, Winter, J, Taylor, J, & Donaldson, N, 1999: Adaptive Interference Reduction (AIR) in Cuff Electrode Recordings, Proc. First Joint BMES/EMBS Conf., 1:419.

A method is presented that significantly reduces residual EMG artefacts in ENG recording systems. The closed-loop system is based on the true-tripole method however here the gains are adjusted automatically to reduce the EMG contamination.

Rieger, R, Taylor, J, Demosthenous, A, Donaldson, N, & Langlois, P J, 2003: Design of a Low-Noise Preamplifier for Nerve Cuff Electrode Recording, IEEE J. Solid-State Circuits, 38(8):1373-1379.

This paper discusses certain important issues involved in the design of a nerve signal preamplifier for implantable neuroprostheses. Since the electroneurogram signal measured from cuff electrodes is typically on the order of 1 µV, a very low-noise interface is essential. We present the argument for the use of BiCMOS technology in this application and then describe the design and evaluation of a complete preamplifier fabricated in a 0.8-µm double-metal double-poly process. The preamplifier has a nominal voltage gain of 100, a bandwidth of 15 kHz, and a measured equivalent input-referred noise voltage spectral density of 3.3 nV/ÖHz at 1 kHz. The total input-referred rms noise voltage in a bandwidth 1 Hz-10 kHz is 290 nV, the power consumption is 1.3 mW from ±2.5-V power supplies, and the active area is 0.3 mm/sup 2/.

Rieger, R, Taylor, J, & Donaldson, N, 2002: Low Noise Preamplifier Design for Nerve Cuff Electrode Recording Systems, IEEE Int'l Symp. Circuits & Sys., 5:193-196.

This paper discusses certain crucial issues involved in the design of a preamplifier for an implantable neural prosthesis. The preamplifier has a nominal gain of 100, a bandwidth of 15kHz and is required to combine very low noise with low power consumption. In particular, due to the low frequencies involved, 1/f noise assumes great significance. We consider three possible architectures for the input stage of the preamplifier: (a) BiCMOS and CMOS in (b) weak and (c) strong inversion. We demonstrate that although the CMOS amplifiers can approach the performance of the BiCMOS circuit, this is only possible at the cost of greater power consumption and enormously increased circuit area. Against these arguments must be set the greater cost of a BiCMOS process.

Sahin, M, 2005: A Low-Noise Preamplifier for Nerve Cuff Electrodes, IEEE Trans. Neur. Sys. & Rehab. Eng.: in press.

A single-stage, low-noise preamplifier is designed using the concept of noise matching for recordings of neural signal with cuff electrodes. The signal-to-noise ratio is approximately 1.6 times higher than that of a low-noise integrated amplifier (AMP-01) for a cuff impedance of 1.5 kW. The bandwidth is 230 Hz - 8.25 kHz (Rs = 2 kW), and the common mode rejection ratio is 91.2 dB at 1 kHz.

Sahin, M, & Durand, D M, 1998: Improved Nerve Cuff Electrode Recordings with Subthreshold Anodic Currents, IEEE Trans. Biomed. Eng., 45(8):1044-1050.

A method has been developed for improving the signal amplitudes of the recordings obtained with nerve cuff electrodes. The amplitude of the electroneurogram (ENG) has been shown to increase with increasing distance between the contacts when cuff electrodes are used to record peripheral nerve activity. The effect is directly related to the propagation speed of the action potentials. Computer simulations have shown that the propagation velocity of action potentials in a length of a nerve axon can be decreased by subthreshold extracellular anodic currents. Slowing the action potentials is analogous to increasing the cuff length in that both result in longer intercontact delays, thus, larger signal outputs. This phenomenon is used to increase the amplitudes of whole nerve recordings obtained with a short cuff electrode. Computer simulations predicting the slowing effect of anodic currents as well as the experimental verification of this effect are presented. The increase in the amplitude of compound action potentials (CAPs) is demonstrated experimentally in an in vitro preparation. This method can be used to improve the signal-to-noise ratios when recording from short nerve segments where the cuff length is limited.

Sahin, M, Durand, D M, & Haxhiu, M A, 1995: Improved Nerve Cuff Electrode Recordings by Sub-Threshold Anodic Currents, IEEE 17th Annual Conf. Eng. in Med. & Biol. Soc., 2:1107-1108.

Computer simulations indicate that the propagation velocity of action potentials in a length of a nerve axon can be decreased by sub-threshold extracellular anodic currents. This phenomenon can be used to increase the amplitude of whole nerve recordings made with a short cuff electrode with circumferencial metal bands, since larger propagation delays between the bands result in larger recorded signals. Computer simulations predicting the slowing effect of anodic currents and experimental data verifying the simulations are presented. The increase in the amplitude of nerve signals (fivefold), recorded experimentally from a short cuff, is demonstrated.

Sinkjaer, T, Hinge, B, Jorgensen, A, Jensen, M L, & Haugland, M, 1992: Whole Sensory Nerve Recordings with Spiral Nerve Cuff Electrode, Proc. 14th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 4:1330-1331.

We have used a self-curling nerve cuff electrode to record sensory information from a cutaneous nerve. This type of cuffs has previously been used only for stimulation, but its mechanical properties could make it very suitable for recording also, since it can be fitted closer to the nerve than traditional cuffs without compromising the nerve. In this study we show that It is possible to record neural signals with at least the same quality as traditional cuffs.

Triantis, I F, & Demosthenous, A, 2004: A High-Performance Adaptive ENG Amplifier, IEEE Int'l Workshop on Biomed. Circuits & Sys., 1-4.

This paper describes an integrated adaptive amplifier for receding electroneurogram (ENG) from tripolar cuff electrodes. The amplifier can automatically compensate for cuff imbalance, thus offering a fully implantable solution to this problem. The circuit was fabricated in 0.8 µm BiCMOS technology with an active area of 0.7 mm . Measured results showed that the ENG amplifier has a cuff imbalance correction range of > ±40%, and a signal-to-interference ratio of about 2/1 (6 dB) even for ±40% imbalance.

Triantis, I F, Demosthenous, A, & Donaldson, N, 2003: Comparison of Three ENG Tripolar Cuff Recording Configurations, Proc. First Int'l IEEE EMBS Conf. Neur. Eng., 364-367.

Cuff electrodes are a safe and reliable technique for long-term recording of the electroneurogram (ENG) from peripheral nerves. However, the usefulness of the recorded ENG depends on the amount of electromyogram (EMG) and stimulus artifact present. Interference cancellation may be offered by tripolar cuff recording configurations, such as the quasi-tripole (QT) and the true-tripole (TT), but in practice their performance is severely degraded by cuff imbalance. The adaptive-tripole (AT) has been developed to compensate for possible cuff imbalance and hence minimize the interference pick-up on the recorded ENG. In this paper, the signal-to-interference ratios of the three tripolar cuff recording configurations are compared in-vivo in the presence of cuff imbalance. The results of the experiments, which were conducted using stimulation-induced signals, indicate that even though two different imbalances were present, the AT outperforms the other two configurations in the majority of cases.

Triantis, I F, Demosthenous, A, Donaldson, N, & Struijk, J J, 2003: Experimental Assessment of Imbalance Conditions in a Tripolar Cuff for ENG Recordings, Proc. First Int'l IEEE EMBS Conf. Neur. Eng., 380-383.

Functional Electrical Stimulation (FES) may be improved by the use of naturally occurring nerve signals as feedback signals. However, the usefulness of the recorded electroneurogram (ENG) signals from nerve cuff electrodes depends on the amount of electromyogram (EMG) interference and stimulus artefact present. Tripolar cuff electrodes reduce interference but suffer from imbalance, which degrades the performance of amplifier recording configurations. Previously cuff imbalance has been mainly associated with impedance variations inside the cuff and cuff asymmetry. In this paper, imbalance is associated with additional factors, including cuff orientation and distance from the interference source. The findings are based on in-vivo and in-vitro experiments performed using a true-tripole amplifier recording system.

Triantis, I, Rieger, R, Taylor, J, & Donaldson, N, 2001: Adaptive Interference Reduction in Nerve Cuff Electrode Recordings, The 8th IEEE Int'l Conf. Electronics, Circuits & Sys., 2:669-672.

Neural signals (ENG) recorded from insulating cuffs fitted with electrodes and placed around nerve bundles may replace artificial sensors in providing feedback signals in functional electrical stimulation (FES) applications. Typical applications include correction of foot-drop, hand grasp in tetraplegic subjects and bladder voiding in certain types of incontinence. Unfortunately, the ENG signal recorded using this method is on the order of a few µV whereas interfering signals can have amplitudes of many mV. Probably the main source of such interference is the Electromyogram (EMG) which is generated by excited muscles near the cuff. A method is presented to reduce the interference pickup in nerve cuff recordings. The gains of differential amplifiers connected to true-tripole nerve cuff recording arrangement are timed adaptively to null the residual EMG. Simulation results show that extraction of the neural signal is possible using this method without the need for additional high order filtering.

Uranga, A, Lago, N, Navarro, X, & Barniol, N, 2004: A Low Noise CMOS Amplifier for ENG Signals, Proc. 2004 Int'l Symp. Circuits & Sys., 4:21-24.

The development of an integrated amplifier, intended to record electrical signals from extracellular peripheral nerves, using cuff electrodes, is presented. In order to minimize the flicker noise generated by the CMOS circuitry, a chopper full differential amplifier is implemented. The amplifier has a gain of 74 dB, a bandwidth of 3 kHz and a power dissipation of 1.3 mWatts, with 5 V power supply. Equivalent input-referred noise level of 6.6 nV/(Hz)/sup 0.5/ has been achieved, obtaining a noise efficiency factor of 5.3, which is clearly competitive, compared with other developed recording amplifiers reported in the literature. The amplifier has been fabricated with a fully CMOS 0.7 µm technology (one poly, two metals, self aligned twin-well CMOS process) and the active area is 2.7 mm/sup 2/. In vivo nerve recordings are provided to demonstrate the feasibility of the amplifier.

Veraart, C, Grill, W M, & Mortimer, J T, 1993: Selective Control of Muscle Activation with a Multipolar Nerve Cuff Electrode, IEEE Trans. Biomed. Eng., 40(7):640-653.

Acute experiments were performed on adult cats to study selective activation of medial gastrocnemius, soleus, tibialis anterior, and extensor digitorium longus with a cuff electrode. A spiral nerve cuff containing twelve dot electrodes was implanted around the sciatic nerve, and evoked muscle twitch forces were recorded in six experiments. Spatially isolated dot electrodes in four geometries (monopolar, longitudinal tripolar, tripolar with four common anodes, and two parallel tripoles) were combined with transverse field steering current(s) from an anode(s) located 180° around from the cathode(s) to activate different regions of the nerve trunk. A selectivity index was used to construct recruitment curves for a muscle with the optimal degree of selectivity. Physiological responses were correlated with the anatomical structure of the sciatic nerve by identifying the nerve fascicles innervating the four muscles, and by determining the relative positions of the electrodes and the nerve fascicles. The results indicated that the use of transverse field steering current improved selectivity. The relative performance of the various electrode arrangements is discussed.

Cuff Electrodes - Signal Processing

Bogdan, M, Schroder, M, & Rosenstiel, W, 2003: Artificial Neural Net Based Signal Processing for Interaction with Peripheral Nervous System, Proc. First Int'l IEEE EMBS Conf. Neur. Eng., 134-137.

Two artificial neural Net (ANN) based signal processing systems processing signals using interfaces to the peripheral nervous system are presented. The aim of the paper is to show ANN's capability to meet requirements needed to interact with the biological nervous system. First, a system for classification of nerve signals is presented. Recordings of nerve signals done by regeneration type neurosensors interfacing the peripheral nerve system are processed by ANNs in order to identify their origin axons from a recorded mixture of several axons. The second system presented is somehow the inverse of the processing system above. In this case, the aim of the signal processing system is to introduce information to the peripheral nervous system by computing appropriate stimulus pattern for functional electrical stimulation. The connection to the peripheral nervous system is done by cuff-electrodes.

Coates Jr., T D, Larson-Prior, L J, Wolpert, S, & Prior, F, 2003: Classification of Simple Stimuli Based on Detected Nerve Activity, IEEE Eng. in Med. & Biol. Magazine, 22(1):64-76.

Describes an interface and a signal processing methodology that use measured neural signals to image overall axonal activity in intact peripheral nerve. Since one of the goals of this research is to create an interface that can eventually be used in both healthy and injured persons, an interfacing methodology that does not rely on nerve transection had to be developed. A cuff electrode containing multiple pairs of differential detectors was used to explore the feasibility of using measured neural signals to image overall axonal activity in intact peripheral nerve. The minimally invasive neural interfacing system (MINIS) consists of four parts: an in vivo multielectrode nerve cuff placed around an intact ensheathed whole nerve, wavelet based signal processing, information-theoretic data summarization, and a cascade correlation neural network. The system was validated using the visual system of Limulus polyphemus (common horseshoe crab). In our application the implantation of the cuff electrode requires surgery to expose the nerve but does not require removal of the sheath and surrounding connective tissue, hence the term "minimally invasive." The trained network for a given specimen was very specific to the specimen-interface-nerve configuration on which the data used to build the training/testing sets originated. When the network becomes overfitted it performs increasingly well at identifying the activity that corresponds to the data on which it was trained while becoming worse with novel data. Though it's doubtful a given source could ever be at the exact centers of all four pairs in a hand-mode cuff, being near the centers impacts the SNR and thus the accuracy for that pattern. Thus far the results are encouraging; however, more work is needed before this system could be used to reliably drive a prosthesis or interact with a virtual environment.

Jezernik, S, 1999: Wiener Filtering and Classification of Neurographic Recordings, Proc. First Joint BMES/EMBS Conf., 1:412.

Methods were developed to improve the S/N ratio and selectivity of nerve recordings, and to allow classification of nerve signals originating from activation of different fiber diameter populations (e.g. different receptors). The need for these methods arose from our `bladder pacemaker' research, where nerve cuff electrodes were placed around the feline sacral spinal roots to monitor urinary bladder afferent activity. A novel technique to design Wiener filters for neurographic recordings was developed, which resulted in improved S/N ratio and selectivity of the recordings. Since the sacral roots innervate dermatomes and the rectum, the nerve signal increases had to be classified to extract bladder afferent information only. Multilayer perceptron neural network was trained with different autocorrelation functions to classify bladder, rectal and cutaneous nerve signal increases.

Jezernik, S, & Grill, W M, 2001: Optimal Filtering of Whole Nerve Signals, J. Neuroscience Methods, 106(1):101-110.

Electroneurographic recordings suffer from low signal to noise (S/N) ratios. The S/N ratio can be improved by different signal processing methods including optimal filtering. A method to design two types of optimal filters (Wiener and Matched filters) was developed for use with neurographic signals, and the calculated filters were applied to nerve cuff recordings from the cat S1 spinal root that were recorded during the activation of cutaneous, bladder, and rectal mechanoreceptors. The S1 spinal root recordings were also filtered using various band- pass (BP) filters with different cut-off frequencies, since the frequency responses of the Wiener and Matched filters had a band-pass character. The mean increase in the S/N ratio across all recordings was 54, 89, and 85% for the selected best Wiener, Matched, and band-pass filters, respectively. There were no statistically significant differences between the performance of the selected filters when all three methods were compared. However, Matched filters yielded a greater increase in S/N ratio than Wiener filters when only two filtering techniques were compared. All three filtering methods have in most cases also improved the selectivity of the recordings for different sensory modalities. This might be important when recording nerve activity from a mixed nerve innervating multiple end- organs to increase the modality selectivity for the nerve fibers of interest. The mean Modality Selectivity Indices (MSI) over different receptor types and for the same selected filters as above were 1.12, 1.27, and 1.29, respectively, and indicate increases in modality selectivity (MSI>1). Improving the S/N ratio and modality selectivity of neurographic recordings is an important development to increase the utility of neural signals for understanding neural function and for use as feedback or control signals in neural prosthetic devices.

Jezernik, S, & Sinkjaer, T, 1999: On Statistical Properties of Whole Nerve Cuff Recordings, IEEE Trans. Biomed. Eng., 46(10):1240-1245.

Whole nerve cuff electrodes can record an electric signal generated by the superposition of single fiber action potentials (APs). Using a simple stochastic model for the superposition of APs, the statistical properties of nerve cuff signals are mathematically derived in this study. Consequences of common signal processing methods like rectification and time-averaging are also explained. The nerve cuff signals are found to be approximately identically, independently distributed Gaussian signals with zero mean and varying variance. The spectral properties of the cuff signals generated by single AP shape or different AP shapes are also addressed and investigated by examining the properties of the autocorrelation functions of the nerve cuff signals. The theoretical results were found to be in accordance with computer simulations and processing of actual recorded data.

Micera, S, Jensen, W, Sepulveda, F, Riso, R R, & Sinkjaer, T, 2001: Neuro-Fuzzy Extraction of Angular Information From Muscle Afferents for Ankle Control During Standing in Paraplegic Subjects: An Animal Model, IEEE Trans. Biomed. Eng., 48(7):787-794.

This paper is part of a project whose aim is the implementation of closed-loop control of ankle angular position during functional electrical stimulation (FES) assisted standing in paraplegic subjects using natural sensory information. Here, a neural fuzzy (NF) model is implemented to extract angular position information from the electroneurographic signals recorded from muscle afferents using cuff electrodes in an animal model. The NF model, named dynamic nonsingleton fuzzy logic system is a Mamdani-like fuzzy system, implemented in the framework of recurrent neural networks. The fuzzification procedure implemented was the nonsingleton technique which has been shown in previous works to be able to take into account the uncertainty in the data. The proposed algorithm was tested in different situations and was able to predict reasonably well the ankle angular trajectories especially for small excursions (as during standing) and when the stimulation sites are far from the registration sites. This suggests it may be possible to use activity from muscle afferents recorded with cuff electrodes for FES closed-loop control of ankle position during quiet standing.

Micera, S, Jensen, W, Riso, R R, & Sinkjaer, T, 1999: Comparison of Different Fuzzy Models to Extract Position Information From Muscle Afferent Activity, Proc. First Joint BMES/EMBS Conf., 1:483.

The aim of this study was to investigate different fuzzy models for joint position prediction using the ElectroNeuroGram (ENG) signals recorded from muscle afferents using cuff electrodes. The Dynamic Non-Singleton Fuzzy Logic System (DNSFLS) model performed best, The good performance of this fuzzy model suggests it might be possible to use activity from muscle afferents recorded with cuff electrodes for Functional Electrical Stimulation (FES) closed-loop control of joint position.

Nakatani, H, Watanabe, T, & Hoshimiya, N, 2001: Detection of Nerve Action Potentials Under Low Signal-To-Noise Ratio Condition, IEEE Trans. Biomed. Eng., 48(8):845-849.

Proposes a method for detection of action potentials (APs) under low signal-to-noise ratio conditions. It is based on multiresolution analysis. Three parameters are used for detection. Two of them are for determining if there is an AP or not, and the other is for the estimation of waveforms. The authors' method provides better estimated waveforms than the conventional de-noising approach.

Nakatani, H, Watanabe, T, Ohba, S, Futami, R, Hoshimiya, N, & Handa, Y, 1999: Classification of Action Potentials Recorded From Peripheral Nerves with Cuff Electrodes, Proc. First Joint BMES/EMBS Conf., 1:484.

In order to extract neural information, action potentials recorded with cuff electrodes from peripheral nerves were classified into unit activities. The classification was performed based on their waveforms, as it was considered that they were affected by the radius of nerve fiber and the distance between fiber and recording electrode. This study focused on automatic classification method. Action potentials were grouped into each unit by hierarchical cluster analysis and a new criterion. The method proposed in this study might be applicable to automatic classification of nerve action potentials, because it provided the reliable estimation of unit activities.

Sepulveda, F, Buskgaard, A, Fjorback, M V, Huber, J B, Jensen, K, & Saigal, R, 2001: Wavelet Packet Analysis for Angular Data Extraction From Muscle Afferent Cuff Electrode Signals, Proc. 23rd Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 2:1352-1355.

Rehabilitation devices can greatly benefit from the use of natural sensors. Thus, we have extended on our efforts to extract angular information from muscle afferent nerves by means of cuff electrodes. Is this study we applied wavelet analysis to electroneurographic (ENG) data from rabbits. In order to estimate ankle flexion/extension angles, we recorded ENG signals from the left Tibial and Peroneal nerves, both during FES and under passive motion. Several processing methods were used for extraction of angular data and were compared with the wavelet analysis. An artificial neural network (ANN) was used with the analyzed features to improve on the accuracy of the angular predictions. The network has so far been tested for local generalization only. The ANN was found to work better with the wavelet features than with previously explored rectified and bin integrated (RBIN) signals. Best results were obtained by using ANN inputs that consisted of both the output from a single wavelet packet node and the RBIN signal: the mean angle prediction error was 1.2°. Exciting as this result is, we must keep in mind that due to the local generalization scope of this study, angle predictions have yet to be assessed regarding inter-rabbit variability.

Struijk, J J, 1997: On the Spectrum of Nerve Cuff Electrode Recordings, Proc. 19th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 5:2006-2007.

The influence of several cuff parameters and electrode configurations on the spectrum of single fiber action potentials in models of nerve cuff recording was analysed. The influence of the cuff is described as a filter with the transmembrane action potential as the input signal.

Tesfayesus, W, Yoo, P, & Durand, D M, 2003: Blind Source Separation of Nerve Cuff Recordings, Proc. 25th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 3:2507-2510.

Nerve Cuff Electrodes record an aggregate signal from a nerve comprised of several fascicles. Recovering individual fascicular signals could be important for the control of prosthetic devices. Blind Source Separation methods have been designed for recovering individual source signals from multi-channel recordings of a mixture of multiple sources. Here, we present a simulation study of the feasibility of applying Blind Source Separation (BSS) to recover fascicular signals from multiple contact nerve cuff electrodes. Spontaneous neuroelectric activities and their recordings are simulated. Hyvarinen's FastICA algorithm, a popular method for BSS, combined with a correlation analysis is used for separation. The ability of the method to separate the fascicular signals was estimated by measuring the correlation between the input and output signals. In 25 random trials with different signals the mean value of the correlation coefficient was 0.86 (± 0.15 S.D.). Although all signals were recovered every time, the algorithm was not able to determine the origin of the signals. The BSS procedure permutes separated signals randomly.

Upshaw, B, & Sinkjaer, T, 1998: Digital Signal Processing Algorithms for the Detection of Afferent Nerve Activity Recorded From Cuff Electrodes, IEEE Trans. Rehab. Eng., 6(2):172-181.

Due to the very poor signal-to-noise ratios (SNR's) usually encountered with whole nerve-cuff signals, the processing method typically applied, rectification and windowed (bin)-integration (RBI), can have serious shortcomings in extracting reliable information. In order to improve detection accuracy, these signals were further analyzed using statistical signal detection algorithms based on their second and higher order spectra (HOS). A comparison with both analog and digital RBI processing suggests that the statistical methods, due to their ability to separate the signal and noise subspaces, are superior. It was determined that the noise typically encountered with nerve-cuff electrode signals is normally (Gaussian) distributed. Therefore, third- order statistics can be applied to, ideally, completely reject the noise component. When cutaneous nerve recordings from the calcaneal nerve (innervating the heel area) were used in a drop-foot correction neural prosthesis, the detection percentage and the insensitivity to algorithm parameters were increased through the use of these statistical methods as to warrant their real-time implementation, and the inherent additional processing hardware that entails.

Upshaw, B, 1996: SVD and Higher-Order Statistics Applied in the Detection of Human Nerve Signal Activity, Proc. IEEE Digital Signal Processing Workshop, 319-322.

Due to the very low signal levels (µV) and the significantly higher levels of interference from adjacent muscles (and other noise sources), the overall signal-to-noise ratios (SNRs) of human nerve signals recorded from whole-cuff electrodes is very poor. Typically, non-real-time methods (ensemble averaging) are used to contend with these poor SNRs. However, if these signals are to be useful in providing real-time information (in a closed-loop control system), other methods must be employed to this end, subspace analysis methods using the eigenvalues of the autocorrelation (a 2nd order statistic) and cumulant (a 3rd order statistic) matrices of time-series samples were evaluated.

Upshaw, B, Rangoussi, M, & Sinkjaer, T, 1996: Detection of Human Nerve Signals Using Higher-Order Statistics, Proc. 8th IEEE Signal Processing Workshop on Statistical Signal & Array Processing, 186-189.

Afferent, whole nerve signals recorded using an implanted nerve-cuff electrode were analyzed using three detectors based on the 1st, 2nd and 3rd order statistical properties of the signals. Results based on standard rectified, bin-integrated (1st order statistical) processing are compared with two algorithms based upon a singular value decomposition (SVD) of the signal's 2nd and 3rd order correlation (cumulant) matrices. Due to the very low signal levels obtainable from nerve-cuff electrodes and the high levels of interference from adjacent muscles, the overall signal-to-noise ratio (SNR) is very poor. In addition, the noise level is non-stationary. The inherent properties of the 3rd order statistics of these signals yield a detector that performs better than the other two.

Upshaw, B, & Sinkjaer, T, 1996: SVD and Higher-Order Statistical Processing of Human Nerve Signals, Proc. 18th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 4:1506-1507.

Human afferent whole nerve signals recorded using an implanted nerve-cuff electrode were analyzed using two algorithms based on the statistical properties of the signals. The processing method typically described in the literature (Rectification and Bin- Integration-RBI) has serious shortcomings in processing these signals, which have very poor signal-to-noise ratios. Algorithms based on a Singular Value Decomposition (SVD) of the signal's 2nd and Higher-Order Statistics (HOS) have resulted in more robust signal detection. Reliable detection of afferent nerve signals is essential if such signals are to be of use in artificial sensory-based functional electrical stimulation neural prosthetics.

Upshaw, B J, & Sinkjaer, T, 1994: Real-Time Digital Signal Processing of Electroneurographic Signals, Proc. 16th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 2:1346-1347.

A battery powered, isolated, digital signal processor (DSP) based system was developed to extract real-time information from electroneurographic (ENG) signals received from a nerve-cuff electrode implanted around the sural nerve of a human subject. The processed ENG signal, acting as an indication of foot contact, has been used to control a functional electrical stimulator (FES) system, in an attempt to correct "drop-foot" gait in a hemiplegically paralyzed, spastic patient. A significant improvement in signal-to-noise ratio over a previous system that was based solely on analog electronics has been achieved through the use of digitally implemented Bessel filters, rectification, and integration.

Winter, J, Rahal, M, Taylor, J, & Donaldson, N, 1999: Blind Separation of EMG and ENG Cuff Electrode Recordings For FES Application, Proc. First Joint BMES/EMBS Conf., 1:581.

ENG signals recorded by cuff electrodes are usually contaminated by EMG activity from nearby muscles. Blind source separation is demonstrated as a method of separating these signals for use with FES applications.

Cuff Electrodes - Signal Generation

Fang, Z P, & Mortimer, J T, 1991: A Method to Effect Physiological Recruitment Order in Electrically Activated Muscle, IEEE Trans. Biomed. Eng., 38(2):175-179.

A stimulation is used to achieve physiological recruitment order of small-to-large motor units in electrically activated muscles. The use of quasitrapezoidal pulses and a tripolar cuff electrode make selective activation of small motor axons possible, thus recruiting slow-twitch, fatigue-resistant muscle units before fast-twitch, fatigable units in a heterogeneous muscle. Isometric contraction force from the medial gastrocnemius muscle was measured in five cats. The physiological recruitment order was evidenced by larger twitch widths at lower force levels and small twitch widths at higher force levels. The force modulation process was more gradual and fused contractions were obtained at lower stimulation frequencies when the proposed stimulation method was used. Muscles activated by the method were more fatigue-resistant under repetitive activation at low force levels. This stimulation method is simpler to implement and has fewer adverse effects on the neuromuscular system than previous blocking methods. It may therefore have applications in future functional neuromuscular stimulation systems.

Fang, Z P, & Mortimer, J T, 1991: Selective Activation of Small Motor Axons by Quasitrapezoidal Current Pulses, IEEE Trans. Biomed. Eng., 38(2):168-174.

A method to activate electrically smaller nerve fibers without activating larger fibers in the same nerve trunk is proposed. The method takes advantage of the fact that action potentials are blocked with less membrane hyperpolarization in larger fibers than in smaller fibers. In this nerve stimulation system, quasitrapezoidal current pulses are delivered through a tripolar cuff electrode to effect differential blocking membrane hyperpolarization. The quasitrapezoidal pulses with a square leading edge, a 350-µs plateau, and an exponential trailing phase ensure the blockage of propagating action potentials and prevent the occurrence of anodal break excitation. The tripolar cuff electrode design restricts current flow inside the cuff and thus eliminates the undesired nerve stimulation due to a virtual cathode. Experiments were performed on 13 cats. The cuff electrode was placed on the medial gastrocnemius nerve. Both compound and single fiber action potentials were recorded from L7 ventral root filaments. The results demonstrate that larger alpha motor axons could be blocked at lower current levels than smaller alpha motor axons, and that all alpha fibers can be blocked at lower current levels than gamma fibers.

Mortimer, J T, Sweeney, J D, Bodner, D R, & Ferguson, A S, 1988: An Implantable Cuff Electrode for Collision Block of Pudendal Nerve Motor Activity, Proc. Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 4:1523-1524.

An implantable cuff electrode technique for collision block of pudendal nerve motor activity has been developed and tested through acute and chronic animal studies. The necessary quasitrapezoidal stimulus parameters for acute and chronic collision block generation have been characterized and are discussed. An asymmetric two-electrode cuff design effectively produces the trains of antidromically propagated action potentials needed to implement a collision block of motor signals to the external periurethral sphincter.

Peng, C W, Chen, J-J J, & Lin, C-C K, 2003: Selective Stimulation on Nerve Fibers by Using High-Frequency Blocking Technique, Proc. First Int'l IEEE EMBS Conf. Neur. Eng., 630-632.

Traditional neural stimulation method recruits the muscle nerves in a reverse order of physiologic manner, i.e., can not recruit small diameter nerve fibers without recruiting large diameter ones. However, high frequency blocking technique is a feasible method for achieving selective stimulation and blocking nerve fibers. The aim of the study is to establish an animal model for studying order recruitment by using high frequency blocking investigation. In this study, a nerve cuff electrode was mounted on sciatic nerve with which two channel of stimulus was delivered for stimulation as well as for high frequency blocking investigation. Furthermore, a torque measurement system was established for assessing the stimulation or blocking performance in this study. Our results shows that varied levels of blocking current can produce gradual change in the blocking effect from 8% of residual torque to more than 90% of maximal torque output. In muscle fatigue test, our results proved that high frequency blocking technique could achieve selective stimulation of smaller nerve fibers and blocking of larger fibers.

Vuckovic, A, Rijkhoff, N J M, & Struijk, J J, 2004: Different Pulse Shapes to Obtain Small Fiber Selective Activation by Anodal Blocking - A Simulation Study, IEEE Trans. Biomed. Eng., 51(5):698-706.

The aim of this study was to investigate whether it is possible to reduce a charge per pulse, which is needed for selective nerve stimulation. Simulation is performed using a two-part simulation model: a volume conductor model to calculate the electrical potential distribution inside a tripolar cuff electrode and a human fiber model to simulate the fiber response to simulation. Selective stimulation is obtained by anodal block. To obtain anodal block of large fibers, long square pulses (>350 µs) with a relatively high currents (1-2.5 mA) are usually required. These pulses might not be safe for a long-term application because of a high charge per pulse. In this study, several pulse shapes are proposed that have less charge per pulse compared with the conventional square pulse and would therefore be safer in a chronic application. Compared with the conventional square pulse, it was possible to reduce the charge with all proposed pulse shapes, but the best results are obtained with a combination of a square depolarizing pulse and a blocking pulse. The charge per pulse was up to 32% less with that pulse shape than with a square pulse. Using a hyperpolarizing anodal prepulse preceding a square pulse, it was not possible to block nerve fibers in a whole nerve bundle and to obtain reduction of a charge per phase. Reduction of the charge could be achieved only with spatially selective blocking. The charge per phase was larger for the combination of a hyperpolarizing anodal prepulse and a two-step pulse than for the two-step pulse alone.

Cortical Electrodes - Biocompatibility and Stability

Becker, T A, & Kipke, D R, 2003: Algel® as a Dural Sealant, Determination of Effects on the Sensori-Motor Cortex in Rats, Proc. 25th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 2:1972-1975.

ALGEL® (Neural Intervention Technologies, Ann Arbor, MI) has shown promise as a biocompatible and mechanically stable material when used as a dural sealant. ALGEL provides a suitable interface between the brain surface and cortical neural implants to help attain long-term neural recordings for over one year in laboratory animals. This paper investigates whether the ALGEL can cause abnormal neural activity or seizures when placed in contact with the motor cortex. Sixteen rats underwent craniotomy procedures and ALGEL and its reactive component, calcium chloride, were placed in contact with the cortex. The response of the animals was evaluated with electroencephalography (EEG) and clinical monitoring of behavior during controlled anesthesia for up to two hours post-application. ALGEL was compared with tranexamic acid (tAMCA), a synthetic fibrinolysis inhibitor that has been shown to cause epileptic seizures. tAMCA, at a dose of 100 mg/ml, showed marked paroxymal brain activity with associated and distinct episodes of jerk-correlated convulsive behaviors. However, various applications of ALGEL on the rat cortex showed no abnormal EEG signals and no episodes of jerk-correlated convulsive behaviors. ALGEL appears to be a safe and effective dural sealant that can be used alone or in combination with neural implants.

Ehteshami, G R, & Massia, S, 2003: Immobilization of Bioactive Peptides on Benzocyclobutene (BCB) Surface Grafted-Dextran for Neural Implant Applications, Proc. 25th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 3:2180-2181.

In vitro cell adhesion and neurite growth on dextran-coated benzocyclobutene (BCB) films, covalently grafted with bioactive peptides are investigated. For cell/tissue adhesive surfaces, synthetic peptide GRGDSP was employed. GRADSP was used as an inactive control for nonspecific peptide-induced cell adhesion. For surface coatings with neurite growth-promoting activity, the laminin-based peptide SRARKQAASIKVAVSADR was utilized. Three cell lines were utilized in these studies. The cell cultures investigated in this study were 3T3 fibroblasts, neuronal-like PC 12 cells, and a glial-like (glioblastoma) T98-G cell line. Chemical composition of all modified surfaces was verified by X-ray photoelectron spectroscopy (XPS). Our non-toxic aqueous methods to graft cell adhesion peptides on dextran monolayer surfaces, effectively limited non- specific cell adhesion and neurite growth in the presence of cultured cells. Microscopic visualization and imaging of these surfaces showed that dextran coatings promoted essentially no adhesion of all cell lines tested. Surface-grafted cell adhesion RGD peptides stimulated fibroblast and glial cell adhesion with minimal neuronal PC12_cell attachment and spreading in vitro. In contrast, surface-grafted inactive RAD peptide sequences did not promote significant cell interaction of all cell types indicating that peptide-grafted surfaces did not promote non-specific cell adhesion. Surface-grafted high affinity IKVAV peptides promoted cell type-dependent interactions. The IKVAV- grafted surfaces also promoted neurite growth on all substrates.

Holecko II, M M, & Massia, S P, 2002: GFAP Inflammatory Response to Dextran-Coated Silicon Electrodes, Proc. Second Joint EMBS/BMES Conf., 3:1832-1833.

Recent advances in three-dimensional, confocal imaging techniques and image analysis software allow for previously unattainable measurements in the neural environment. Specifically, relative quantitative measurements of the amount of glial fibrillary acidic protein (GFAP) surrounding a neural implant can be determined. In this study, dextran coatings have been applied to silicon neural implants. Dextran coatings have been shown to limit non-specific cell adhesion in vitro. Thus, it is believed that these coatings will limit the amount of gliosis surrounding a neural implant and ultimately improve signal-to-noise ratio. To test this hypothesis, Sprague-Dawley rats were implanted with both dextran-coated and non-dextran-coated silicon electrodes. Using immunohistochemical staining in conjunction with confocal imaging and image analysis techniques, the differences in GFAP upregulation between dextran-coated and non-treated silicon neural implants were investigated.

Khang, D, McKenzie, J L, & Webster, T J, 2004: Carbon Nanofibers: Polycarbonate Urethane Composites as a Neural Biomaterial, Proc. IEEE 30th Annual Northeast Bioengineering Conf., 241-242.

Chronic neural implants are usually made from silicon materials and are subject to scar tissue formation at the tissue/implant interface, which interferes with their functionality. Carbon nanofibers are an example of a material that may improve neural implant interactions with native cell populations since these nanofibers have promising cytocompatibility, mechanical, and electrical properties. Neural implants may achieve better tissue interactions simply by incorporating carbon nanofibers into a polymer matrix. Polycarbonate urethane and carbon nanofiber composites have induced neurite extension during in vitro studies. The objective of the present study was to use an electrical field to align carbon nanofibers in a polycarbonate urethane matrix. Polycarbonate urethane was dissolved in chloroform, and then mixed with carbon nanofibers of high and low surface energies separately. When the solution was viscous, it was pored into a parallel copper plate capacitor chamber. Alignment occurred after exposure to 500 to 700 volts. The aligned nanofiber structure was maintained after the polymer cured. These materials have been prepared to determine if neuron axonal extension will be affected by the carbon nanofiber alignment. These materials have promising tunable properties for neural implants such as electrical, nanoscale structure and organization, and surface energy characteristics.

Stice, P J, Panitch, A, & Muthuswamy, J, 2003: Improved Viability of Chronic Neural Implants using Thin Microelectrodes, Proc. 25th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 2:1987-1989.

The recording interface between neurons and an implanted microelectrode recording site is often compromised due to gliosis, rendering the implant nonfunctional under chronic conditions. The objective of this project is to design novel microelectrodes that will minimize gliosis under chronic implantation. We test the hypothesis that gliosis can be minimized or eliminated by reducing the cross-sectional area of the chronic implant. Current microelectrodes for recording chronic action potentials range from 25 µm to 100 µm or more in diameter. We fabricated neural implants by coating 12 µm stainless steel microwires with polyglycolic acid (PGA), a biodegradable polymer, resulting in a final diameter of 25 µm. Twelve rats were implanted with the PGA coated electrode on the left hemisphere in the somatosensory cortex and with the regular 25 µm stainless microelectrode in the right hemisphere. The rat brains were perfused at 4 weeks after implantation and stained for glial fibrilliary acidic protein (GFAP) and microtubule associated protein-2 (MAP-2). The microelectrodes coated with PGA produced minimal gliosis compared to the conventional 25 µm wire and other silicon based microelectrodes. We conclude that ultra-thin neural implants with minimum cross- sectional area coated with PGA will greatly improve the functionality of microelectrodes under chronic conditions.

Zhong, Y, Connell, M, C, G, Ross, J D, Weerth, D, , S P, & Bellamkonda, R V, 2005: A Novel Dexamethasone-Releasing, Anti-Inflammatory Coating for Neural Implants, Proc. 2nd Int'l IEEE EMBS Conf. Neur. Eng., 522-525.

The long-term stability of implanted micromachined neural probes is compromised due to the glial scar formation at the insertion site. In this study, we developed a novel nitrocellulose-based coating for the sustained local delivery of the anti-inflammatory drug dexamethasone, a synthetic glucocorticoid that effectively reduces inflammation in the CNS. In vitro dexamethasone release was observed over 16 days, with a relatively high release in the first three days and a slow, stable release thereafter. When Michigan neural recording probes coated with and without dexamethasone-loaded nitrocellulose coatings were implanted into the adult rat brains, immunohistochemical evidence shows a marked reduction of reactive astrocytes (GFAP), reactive microglia (ED1), and chondroitin sulfate proteoglycans (CS56) expression around the insertion site compared to uncoated probes. Impedance spectroscopy showed that the dexamethasone-loaded nitrocellulose coatings slightly reduce the magnitude of electrode impedance at the biologically relevant frequency of 1 kHz through an increase of capacitance. In vivo acute recordings demonstrate that extracellular recordings with coated probes are akin to non-coated probes and it is anticipated that with time, the coated probes will exhibit superior performance. In conclusion, we developed a novel nitrocellulose-based, drug releasing coating for neural electrodes that can effectively reduce scar tissue formation without adversely affecting the electrical performance of the electrodes.

Cortical Electrodes - Design and Fabrication

Clement, R S, Singh, A, Olson, B, Lee, K, & He, J, 2003: Neural Recordings From a Benzocyclobutene (BCB) Based Intra-Cortical Neural Implant in an Acute Animal Model, Proc. 25th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 3:2176-2179.

Multi-channel micro-electrode arrays provide unmatched spatio-temporal resolution for assessing the activity of populations of neurons. These neural implants provide a powerful tool for developing a better understanding of cortical processing, as well as provide an intimate interface for neuroprosthetic applications. Over the years, micro- wire based devices that are manufactured by hand, have allowed researchers to record for several months, and in rare cases up to a year or more. Devices based on microelectro-mechanical systems (MEMs) offer more controlled designs with the added benefit of batch fabrication. Polymer-based MEMs interfaces offer exciting promise over traditional silicon arrays due to their mechanical flexibility and excellent biocompatibility. In this paper we microfabricated a neural interface using a new class of polymer known as benzocyclobutene (BCB), developed for microelectronics under the trade name Cyclotene™. This polymer has properties that we believe make it an attractive candidate for chronic implant applications. We ---provide for the first time a quantitative assessment of its recording capability in an acute animal model. Continuous recordings of neural signals (100 µV) from barrel cortex of a rat were successfully demonstrated. These results are encouraging for further development of a long term implant based on BCB.

Fofonoff, T A, Martel, S M, Hatsopoulos, N G, Donoghue, J P, & Hunter, I W, 2004: Microelectrode Array Fabrication by Electrical Discharge Machining and Chemical Etching, IEEE Trans. Biomed. Eng., 51(6):890-895.

Wire electrical discharge machining (EDM), with a complementary chemical etching process, is explored and assessed as a method for developing microelectrode array assemblies for intracortically recording brain activity. Assembly processes based on these methods are highlighted, and results showing neural activity successfully recorded from the brain of a mouse using an EDM-based device are presented. Several structures relevant to the fabrication of microelectrode arrays are also offered in order to demonstrate the capabilities of EDM.

Jeantet, Y, & Cho, Y H, 2003: Design of a Twin Tetrode Microdrive and Headstage for Hippocampal Single Unit Recordings in Behaving Mice, J. Neuroscience Methods, 129(2):129-134.

A new, easy to construct electrode, microdrive and headstage for electrophysiological recording system which is specifically adapted for freely behaving mice is described. The system uses printed circuit boards and light, flexible cables to enable the animal's free movement for behavioral testing. A clip attachment system permits rapid and secure connection of the headstage and cables to the microdrive assembly on the animal's head. The current system provides eight recording channels, but the design can be modified to accommodate additional channels.

Jog, M S, Connolly, C I, Kubota, Y, Iyengar, D R, Garrido, L, Harlan, R, & Graybiel, A M, 2002: Tetrode Technology: Advances in Implantable Hardware, Neuroimaging, and Data Analysis Techniques, J. Neuroscience Methods, 117(2):141-152.

The technical advances in hardware and software for multiunit recordings have made it easier to gather data from a large number of neurons for behavioral correlations. This paper discusses several such advances in implantable hardware, magnetic resonance imaging of electrodes in situ, and data analysis software for multiple simultaneous signals.

Keating, J G, & Gerstein, G L, 2002: A Chronic Multi-Electrode Microdrive for Small Animals, J. Neuroscience Methods, 117(2):201-206.

We describe a simple microdrive device appropriate for chronic microelectrode recording in rats. No precision machining is required; all parts are stock or cut from standard stock material with hand tools and assembled with epoxy. The device together with its electrodes can be discarded at the completion of the experiment.

Kipke, D R, Vetter, R J, Williams, J C, & Hetke, J F, 2003: Silicon-Substrate Intracortical Microelectrode Arrays for Long-Term Recording of Neuronal Spike Activity in Cerebral Cortex, IEEE Trans. Neur. Sys. & Rehab. Eng., 11(2):151-155.

This study investigated the use of planar, silicon-substrate microelectrodes for chronic unit recording in the cerebral cortex. The 16-channel microelectrodes consisted of four penetrating shanks with four recording sites on each shank. The chronic electrode assembly included an integrated silicon ribbon cable and percutaneous connector. In a consecutive series of six rats, 5/6 (83%) of the implanted microelectrodes recorded neuronal spike activity for more than six weeks, with four of the implants (66%) remaining functional for more than 28 weeks. In each animal, more than 80% of the electrode sites recorded spike activity over sequential recording sessions during the postoperative time period. These results provide a performance baseline to support further electrode system development for intracortical neural implant systems for medical applications.

Kipke, D R, Pellinen, D S, & Vetter, R J, 2002: Advanced Neural Implants Using Thin-Film Polymers, IEEE Int'l Symp. Circuits & Sys., 4:173-176.

BioMEMS devices can be designed to provide viable neural interfaces for long-term, high-density, two-way communication with selected areas of cerebral cortex. Prototype thin-film polymer implantable microelectrode arrays were developed to extend the microelectrode design space in several ways, including enhanced flexibility, engineered surfaces and coatings, and new types of microchannels. Prototype MEMS silicon microdevices were developed as microsurgical tools for reliably inserting the flexible polymer electrodes into the cerebral cortex. Hybrid polymer microdevices were also developed for neural recording and stimulation combined with micro-drug delivery.

Lee, K-K, He, J, & Wang, L, 2004: Benzocyclobutene (BCB) Based Neural Implants with Microfluidic Channel, Proc. 26th Annual Int'l Conf. Eng. in Med. & Biol. Soc., 6:4326-4329.

Benzocyclobutene (BCB) based intracortical neural implants for basic neuroscience research in animal models was fabricated, in which microfluidic channel was embedded to deliver chemical reagents. BCB presents several attractive features for chronic applications: flexibility, biocompatibility, desirable chemical and electrical properties, and can be easily manufactured using existing batch microfabrication technology; The fabricated implants have single shank with three recording sites (20 µ 20 µm) and two reservoirs (inlet and outlet). The channel had large volume (40 µm width and 10 µm height), and hydrophobic surface to provide a high degree of chemical inertness. All the recording sites were positioned near the end of the shank in order to increase the probability of recording neural signals from a target volume of tissue. In vitro biocompatibility tests of fabricated implants revealed no adverse toxic effects on cultured cells. The implant with a 5 µm silicon backbone layer penetrated rat's pia without buckling, a major drawback of polymer alone. The averaged impedance value at 1 kHz was ~1.2 MW. Water flowing through the channel was observed. Depending on the amount of the driving pressure from the syringes, the delivery speed of the water was totally controlled.

Lee, K-K, He, J, Singh, A, & Kim, B, 2003: Benzocyclobutene (BCB) Based Intracortical Neural Implant, Proc. Int'l Conf. MEMS, NANO & Smart Sys., 418-422.

A novel structure for chronically implantable cortical electrodes using new Benzocyclobutene (BCB) bio-polymer was devised, which provides both flexibility for micro-motion compliance between brain tissues and skull and stiffness for better surgical handling. BCB is very attractive polymer for stable long-term implant function, because it has flexibility, biocompatibility, low moisture uptake (<0.2 wt%), and low dielectric constant (~2.6). For easy operation during surgical insertion, a 5~10µm thick silicon backbone layer is attached to the desired region of the electrode to increase the stiffness. It is then followed by 1 mm of flexible part of the electrode without silicon backbone layer designed to absorb stress from any micro-motion between the brain tissue and the electrode. The fabricated implants have tri-shanks with 5 recording sites (20×20 µm) and 2 vias (40×40 µm) on each shank. BCB electrodes with 5µm and 10µm thick backbone silicon penetrated pia of rat brain without buckling.

Lee, K-K, Singh, A, Zhu, H, Coryell, G, Olson, B, Kim, B, Raupp, G, & He, J, 2003: Fabrication of Implantable Polyimide Based Neural Implants with Flexible Regions to Accommodate Micromovement, Proc. 12th Int'l Conf. Transducers, Solid-State Sensors, Actuators & Microsystems, 2:1221-1224.

A unique structure for chronically implantable cortical electrodes using polyimide polymer was devised, which provides both flexibility between brain tissues and skull and stiffness for easy insertion. The fabricated implants are tri-shanks with 5 recording sites (20×20 µm) and 2 vias per electrode of 40×40 µm. Each recording site was connected to the external circuitry via a 15-channel connector, which is especially designed to facilitate processing of neural signals to the external circuitry. Measured impedance values are in ~2 Mohm at 1 KHz. For a 5 µm thick silicon backbone electrode, the stiffness was improved 10 times larger than that of the electrode without silicon backbone layer. Stiff electrodes with 5 µm and 10 µm thick backbone silicon penetrated pia of rat without buckling.

Muthuswamy, J, Gilletti, A, Jain, T, & Okandan, M, 2003: Microactuated Neural Probes to Compensate for Brain Micromotion, Proc. 25th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 2:1941-1943.

One of the dominant failure modes of chronic neural implants is micromotion of the surrounding brain tissue relative to the implant leading to neuronal drift and shear injury. In this study, we have (a). Assessed the micromotion in the somatosensory cortex and (b). Designed, developed and tested a microactuated neural probe that can compensate for brain micromotion. We used a differential variable reluctance (DVRT) transducer in adult rats (n=8) to monitor micromotion in the somatosensory cortex. Electrostatic microactuators were fabricated using the SUMMiT (Sandia's Ultraplanar Multilevel MEMS Technology) process, a 5-layer polysilicon micromachining technology of the Sandia National labs, NM. In anesthetized rats, surface micromotion was observed to be in the order of 2-25 µm due to pressure changes during respiration and 1-3 µm due to vascular pulsatilily. In addition there were long-term drifts in the order of 80 µm due to changes in the anesthetic level. The microactuated neural probe was capable of moving in steps of 1µm with an aggregate translational capability in the order of several millimeters. In conclusion, there is significant micromotion in the surface of the somatosensory cortex that could lead to failure of chronic neural implants. Microactuated neural probes are capable of compensating for this micromotion.

Rousche, P J, Pellinen, D S, Pivin Jr., D P, Williams, J C, Vetter, R J, & Kipke, D R, 2001: Flexible Polyimide-Based Intracortical Electrode Arrays with Bioactive Capability, IEEE Trans. Biomed. Eng., 48(3):361-371.

The promise of advanced neuroprosthetic systems to significantly improve the quality of life for a segment of the deaf, blind, or paralyzed population hinges on the development of an efficacious, and safe, multichannel neural interface for the central nervous system. The candidate implantable device that is to provide such an interface must exceed a host of exacting design parameters. The authors present a thin-film, polyimide-based, multichannel intracortical Bio-MEMS interface manufactured with standard planar photo-lithographic CMOS-compatible techniques on 4-in silicon wafers. The use of polyimide provides a mechanically flexible substrate which can be manipulated into unique three-dimensional designs. Polyimide also provides an ideal surface for the selective attachment of various important bioactive species onto the device in order to encourage favorable long-term reactions at the tissue-electrode interface. Structures have an integrated polyimide cable providing efficient contact points for a high-density connector. This report details in vivo and in vitro device characterization of the biological, electrical and mechanical properties of these arrays. Results suggest that these arrays could be a candidate device for long-term neural implants.

Singh, A, Zhu, H, & He, J, 2004: Improving Mechanical Stiffness of Coated Benzocyclobutene (BCB) Based Neural Implant, Proc. 26th Annual Int'l Conf. Eng. in Med. & Biol. Soc., 6:4298-4301.

We briefly report recent results of a simple alternate method to improve mechanical stiffness of BCB polymer neural implant for surgical insertion into brain tissue, which uses coatings dissolvable in bio-fluids. We have studied three different coating materials such as thermo-reversible gel Poloxamer 407, glucose (C/sub 6/H/sub 12/O/sub 6/) and regular table sugar that were applied by dip coating onto the implant surface. The preliminary results of this study have shown that coating BCB probes with Poloxamer 407 polymer, a thermo-reversible gel, or table sugar significantly improves the buckling strength. However, the table sugar coating provides the greatest increase in stiffness, which is sufficient to penetrate both the preserved and live brain tissues without buckling.

Singh, A, Lee, K-K, He, J, Ehteshami, G, Massia, S, & Raupp, G, 2003: Benzocyclobutene (BCB) Based Intracortical Neural Implant, Proc. 25th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 4:3364-3367.

Photosensitive benzocyclobutene (photo-BCB) is a class of photoimagable polymers developed for microelectronics under the trade name Cyclotene™ with properties that we believe make it an attractive candidate for chronic implant applications. We report for the first time a complete microfabrication process of BCB polymer-based intracortical neural implant for chronic application. The new design of the implant provides flexibility for micromotion compliance at the brain/implant interface and the necessary stiffness for better surgical handling. We have demonstrated that the implant with a silicon backbone layer of 5~10 µm is robust enough to penetrate the pia without buckling, a major drawback with polymer. The averaged impedance value at 1 KHz was ~250 KW.

Szabó, I, Czurkó, A, Csicsvari, J, Hirase, H, Leinekugel, X, & Buzsįki, G, 2001: The Application of Printed Circuit Board Technology for Fabrication of Multi-Channel Micro-Drives, J. Neuroscience Methods, 105(1):105-110.

A modular multichannel microdrive ('hyperdrive') is described. The microdrive uses printed circuit board technology and flexible fused silica capillaries. The modular design allows for the fabrication of 4-32 independently movable electrodes or 'tetrodes'. The drives are re-usable and re-loading the drive with electrodes is simple.

Williams, J C, & Kipke, D R, 1999: Methods for Modeling the Relationship Between Extracellular Recording Variability and Impedance Properties of Chronic Neural Implants, Proc. First Joint BMES/EMBS Conf., 1:486.

A finite element model has been developed to investigate the theoretical relationship between changes in extracellular resistivity and electrical potential in a chronic extracellular recording scenario. The inputs to the model are experimental results obtained from chronic recording and complex impedance measurements in cerebral cortex of adult guinea pigs. Using the measured tissue-electrode impedance to set the resistivity in the model provides simulated extracellular potentials that are consistent with the measured spike amplitudes. In both the experimental and theoretical paradigms it was found that increased extracellular resistivity results in an increased potential at the recording electrode tip. Although the results of the two methods could not be directly correlated, they do suggest that a certain amount of variance can be accounted for by the increased resistivity values. The methods presented offer a powerful theoretical tool for understanding some of the factors, which may affect chronic extracellular recording stability.

Zhu, H, He, J, & Kim, B, 2004: High-Yield Benzocyclobutene(BCB) Based Neural Implants for Simultaneous Intra- and Extracortical Recording in Rats, Proc. 26th Annual Int'l Conf. Eng. in Med. & Biol. Soc., 6:4341-4344.

A unique structure for chronically implantable cortical electrodes based on benzocyclobutene (BCB) biopolymer was designed to perform intracortical and extracortical neural recording simultaneously in basic neuroscience research using animal models. It was fabricated on silicon wafer using standard planar CMOS surface microfabrication technique. Dry-etchable BCB was used to insulate the electrode and provide flexibility for micro-motion compliance between brain tissue and skull. This electrode is also designed to ease the handling and implantation during the surgery and to integrate buffer circuits to improve the signal-to-noise ratio. The reliable fabrication process was developed to improve the electrode yield and performance. A 15 µm thick tungsten layer was sandwiched in the electrode tip to improve the stiffness for easy insertion during the surgery. The fabricated electrodes have two intra-cortical recording sites (20×20 µm) in the tip penetrating into the cortex and two epidural recording sites (80×80 µm) on each side wing, providing a 6 channel system. One via (40×40 µm) was also incorporated in the tip to balance the tip and provide the bio-seeding to improve the implants and neural tissue interaction. The acute surgical testing suggests that this electrode structure can penetrate the pia into the cortical tissue without damaging the electrode.

Hook Electrodes - Biocompatibility and Stability

Hook Electrodes - Design and Fabrication

Gruhn, M, & Rathmayer, W, 2002: An Implantable Electrode Design for Both Chronic in Vivo Nerve Recording and Axon Stimulation in Freely Behaving Crayfish, J. Neuroscience Methods, 118(1):33-40.

A chronically implantable electrode design permitting alternate extracellular nerve recording and axon stimulation in freely behaving crayfish was developed. The electrode consists of a double hook made from 20 µm thin platinum wire that can be fitted to various nerve diameters, and is easily implantable. A fast curing, flexible two- component silicone was used for insulation. The double hook was connected to plugs and fixed on the carapace of a crayfish allowing the animals to roam freely. The setup also allows for repeated dis- and re-connection of the crayfish for alternating recording and stimulation. Two channel recordings were used to determine directionality and to discriminate between afferent activity of the two stretch receptor neurons and efferent activity of several motor neurons. In addition, they were also used to determine the conduction velocity of the recorded efferent activity. Stable two-channel recordings could be obtained for up to 5 months and 15 days without apparent effects on the animal. In vivo stimulation could be performed for at least 3 weeks. The implantable double hook is suitable for widespread use in invertebrate neurobiology.

Sieve Electrodes - Biocompatibility and Stability

Klinge, P M, Vafa, M A, Brinker, T, Brandis, A, Walter, G F, Stieglitz, T, Samii, M, & Wewetzer, K, 2001: Immunohistochemical Characterization of Axonal Sprouting and Reactive Tissue Changes After Long-Term Implantation of a Polyimide Sieve Electrode to the Transected Adult Rat Sciatic Nerve, Biomaterials, 22(17):2333-2343.

The development of artificial microstructures suited for interfacing of peripheral nerves is not only relevant for basic neurophysiological research but also for future prosthetic approaches. Aim of the present study was to provide a detailed analysis of axonal sprouting and reactive tissue changes after implantation of a flexible sieve electrode to the proximal stump of the adult rat sciatic nerve. We report here that massive neurite growth after implantation, steadily increasing over a period of 11 months, was observed. Parallel to this increase was the expression of myelin markers like Po, whereas non-myelin-forming Schwann cells did not change. Compared to five weeks post-implantation, where both Schwann-cell phenotypes were intermingled with each other, non-myelin-forming Schwann cells occupied a peripheral position in each microfascicle after 11 months. After an initial increase, hematogenous macrophages were down-regulated in number but maintained close contact with the implant. However, at no time were signs of its degradation observed. It is concluded that the introduced flexible polyimide electrode is suitable for contacting peripheral nerves since it permits substantial neurite growth and offers excellent long-term stability.

Sieve Electrodes - Design and Fabrication

Kawada, T, Zheng, C, Tanabe, S, Uemura, T, Sunagawa, K, & Sugimachi, M, 2004: A Sieve Electrode as a Potential Autonomic Neural Interface for Bionic Medicine, Proc. 26th Annual Int'l Conf. Eng. in Med. & Biol. Soc., 2:4318-4321.

We examined the applicability of a sieve electrode to the autonomic nervous system as a potential neural interface for bionic medicine. We developed, using a Si- semiconductor process, a sieve electrode having a square diaphragm (1 mm in one side, 12 µm in thickness) with 30-81 penetrating square holes (50-100 µm in one side). In the first protocol, we implanted the sieve electrode to the vagal nerve in rats. One hundred and twenty days after the implantation, cuff electrodes were attached to the vagal nerve proximal and distal to the sieve electrode under halothane anesthesia. The evoked action potential was recorded from the sieve electrode by nerve stimulation via the cuff electrodes. The evoked action potential was also recorded from the cuff electrodes by nerve stimulation via the sieve electrode. In the second protocol, we implanted the sieve electrode to the renal sympathetic nerve in rabbits. Forty days after the implantation, the spontaneous action potential or sympathetic nerve activity was recorded under pentobarbital anesthesia. In conclusion, we were able to record the evoked and spontaneous action potentials using the sieve electrode. The sieve electrode will provide a useful neural interface for recording and stimulating the autonomic nervous system.

Wallman, L, Levinsson, A, Schouenborg, J, Holmberg, H, Montelius, L, Danielsen, N, & Laurell, T, 1998: Silicon Sieve Electrodes for Neural Implants-In Vitro Characterisation and in Vivo Recordings, Proc. 20th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 4:2225-2228.

An in vitro model was developed to characterise the electrical properties of silicon microfabricated recording electrodes, using a Cu-wire mimicing a neural signal source. Phosphorous doped electrodes were used to achieve an all silicon device. The model was used to study signal amplitude as a function of distance between the electrode surface and the signal source. Signal crosstalk to neighbouring electrodes on the chips were recorded. The crosstalk was found to be 6 dB using an external reference electrode. Improvements were accomplished with an on-chip reference electrode giving an amplitude crosstalk suppression of 20 dB. It was found that the amplitude decreased by a factor of 2 at a distance of 50 µm between the electrode surface and the signal source. Sieve electrodes were also implanted in the rat sciatic nerve and following a 10 week nerve regeneration period the dorsal and ventral (L5) roots in the spinal cord were stimulated. Compound action potentials were recorded via the chip. Lower leg muscle contraction activity was also induced by stimulating the regenerated sciatic nerve via the sieve electrode.

Functional Electrical Stimulation

Andreasen, L N S, & Struijk, J J, 2003: Skin Contact Forces Extracted From Human Nerve Signals - A Possible Feedback Signal for FES-Aided Control of Standing, IEEE Trans. Biomed. Eng., 50(12):1320-1325.

Information about stance related skin contact forces was extracted from nerve cuff electrode recordings of human neural signals. Forces measured under the heel during standing were scaled and applied to the innervation area of the sural nerve on the side of the foot using a hand held force probe. The neural response to the stimuli was measured with a cuff chronically implanted around the sural nerve in one hemiplegic person. An artificial neural network was used for extraction of the applied force from the recorded nerve signal. The results showed that it is possible to extract information about absolute skin contact forces from the nerve signal with an average goodness of fit of 69.3% for all trials and 82.2% for the more dynamic trials. This information may be applicable as a feedback signal in control of standing.

Andreasen, L N S, Jensen, W, Veltink, P H, & Struijk, J J, 1996: Natural Sensory Feedback for Control of Standing, Proc. 18th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 1:441-442.

The use of natural sensory signals as feedback for FES systems within rehabilitation is still in its early stage. So far the signals have mostly been used for event detection, e.g, detection of slip. A new application of sensory feedback signals is to apply it in control of paraplegic standing, This paper describes a preliminary study to the use of natural sensory feedback in control of FES assisted standing. It was investigated whether it seems possible to extract a qualitative feature suitable for control of standing from an ENG signal recorded by a cuff electrode. The ENG from the foot sole of one normal subject, standing with voluntary sway, was modeled and used for extraction of the center of pressure (COP) within the foot support area. An artificial neural network was used for feature extraction and the extracted COP was compared with the actual COP measured by a forceplate. The result showed that the modeled ENG signal does provide information about the position of COP.

Haugland, M, Lickel, A, Haase, J, & Sinkjaer, T, 1999: Control of FES Thumb Force Using Slip Information Obtained From the Cutaneous Electroneurogram in Quadriplegic Man, IEEE Trans. Rehab. Eng., 7(2):215-227.

A tetraplegic volunteer was implanted with percutaneous intramuscular electrodes in hand and forearm muscles. Furthermore, a sensory nerve cuff electrode was implanted on the volar digital nerve to the radial side of the index finger branching off the median nerve. In laboratory experiments a stimulation system was used to produce a lateral grasp (key grip) while the neural activity was recorded with the cuff electrode. The nerve signal contained information that could be used to detect the occurrence of slips and further to increase stimulation intensity to the thumb flexor/adductor muscles to stop the slip. Thereby the system provided a grasp that could catch an object if it started to slip due to, for example, decreasing muscle force or changes in load forces tangential to the surface of the object. This method enabled an automatic adjustment of the stimulation intensity to the lowest possible level without loosing the grip and without any prior knowledge about the strength of the muscles and the weight and surface texture of the object.

Haugland, M, & Lickel, A, 1998: Improved Method for Use of Natural Sensory Feedback in Control of Grasp Force for Stimulated Hand Muscles, Proc. 20th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 5:2310-2312.

Functional electrical stimulation of paralyzed hands can provide the user with some basic hand function. To improve the grasp provided by this method it is being attempted to use information from natural cutaneous sensors as recorded by a nerve cuff electrode implanted around a peripheral nerve. Slips across the skin can be detected in the nerve signal. This can be used to provide automatic intervention if an object being held starts to slip. A method for estimating the proper intensity of the reaction to a slip is presented. The method is based on the assumption that the reaction intensity should increase with the velocity of the slip and that the velocity is reflected in the amplitude of the nerve signal.

Haugland, M K, & Hoffer, J A, 1994: Slip Information Provided by Nerve Cuff Signals: Application in Closed-Loop Control of Functional Electrical Stimulation, IEEE Trans. Rehab. Eng., 2(1):29-36.

A model of a paralyzed hand gripping and lifting an object was developed using anaesthetized cats. Functional neuromuscular stimulation (FNS) applied to the ankle plantarflexor muscles caused the footpad to press against and grip an object. Electroneurographic activity (ENG) activity generated by skin mechanoreceptors in the footpad was recorded with a cuff electrode implanted on the tibial nerve. Sharp bursts evident in the ENG signaled any slips between the object and the skin. This information was used in an event-driven controller that allowed the FNS system to compensate for slips. In this way an "artificial gripping reflex" was implemented that compensated automatically for internal changes (fatigue) and the external perturbations (increased load, changed frictional coefficient). This control scheme proved to be robust and is proposed to be applicable for restoration of precision grip in paralyzed humans.

Haugland, M K, Hoffer, J A, & Sinkjaer, T, 1994: Skin Contact Force Information in Sensory Nerve Signals Recorded by Implanted Cuff Electrodes, IEEE Trans. Rehab. Eng., 2(1):18-28.

When functional neuromuscular stimulation (FNS) is used to restore the use of paralyzed limbs after a spinal cord injury or stroke, it may be possible to control the stimulation using feedback information relayed by natural sensors in the skin. In this study the authors tested the hypothesis that the force applied on glabrous skin can be extracted from the electroneurographic (ENG) signal recorded from the sensory nerve. They used the central footpad of the cat hindlimb as a model of the human fingertip and recorded sensory activity with a cuff electrode chronically implanted around the tibial nerve. Their results showed that the tibial ENG signal, suitably filtered, rectified, and smoothed carries detailed static and dynamic information related to the force applied on the footpad. The authors derived a mathematical model of the force-ENG relation that provided accurate estimates of the ENG signal for a wide range of force profiles, amplitudes, and frequencies. Once fitted to data obtained in one recording session, the model could be made to fit data obtained in other sessions from the same cat, as well as from other cats, by simply adjusting its overall gain and offset. However, the model was noninvertible; i.e., the force could not be similarly predicted from the ENG signal, unless additional assumptions or restrictions were introduced. The authors discuss the reasons for these findings and their implications on the potential use of nerve signals as a source of continuous force feedback information suitable for closed-loop control of FNS.

Hoffer, J A, Haugland, M, & Li, T, 1989: Obtaining Skin Contact Force Information From Implanted Nerve Cuff Recording Electrodes, Proc. Annual Int'l Conf. IEEE Eng. in Eng. in Med. & Biol. Soc., 3:928-929.

An investigation was conducted to determine how the electrical activity in a cutaneous nerve relates to the force applied on glabrous skin. Nerve cuff electrodes implanted on the tibial nerve of cats were used to record the electroneurogram (ENG) when the footpad was probed by a servo-controlled motor. The ENG signal was nonlinearly dependent on the applied force. It saturated for high forces, adapted when constant forces were applied, and was very sensitive to slippage. Linear system identification techniques provided estimates of force amplitude and frequency. Improved estimates were obtained using a real-time, analog, nonlinear filter that included proportional integral and exponential terms. Accurate estimations of input force could best be made if the force was not constant but varied in the 0.1-5.0-Hz range. Cuff electrodes implanted on nerves supplying glabrous skin of the hands or feet may provide feedback suitable, for example, for the closed-loop control of functional electrical simulation of paralyzed muscles in spinal cord injured patients.

Jensen, W, Lawrence, S M, Riso, R R, & Sinkjaer, T, 2001: Effect of Initial Joint Position on Nerve-Cuff Recordings of Muscle Afferents in Rabbits, IEEE Trans. Neur. Sys. & Rehab. Eng., 9(3):265-273.

The objective was to characterize nerve-cuff recordings of muscle afferents to joint rotation over a large part of the physiological joint range. This information is needed to develop control strategies for functional electrical stimulation (FES) systems using muscle afferent signals for sensory feedback. Five acute rabbit experiments were performed. Tripolar cuff electrodes were implanted around the tibial and peroneal divisions of the sciatic nerve in the rabbit's left leg. The electroneurograms (ENG) were recorded during passive ankle rotation, using a ramp-and-hold profile starting at seven different joint positions (excursion=5°, velocity=10°/s, initial positions 60°, 70°, 80°, 90°, 100°, 110°, and 120°). The amplitude of the afferent activity was dependent on the initial joint position. The steady-state sensitivity of both nerve responses increased with increasing joint flexion, whereas the dynamic sensitivity increased initially but then decreased. The results indicate that recordings of the muscle afferents may provide reliable information over only a part of the physiological joint range, Despite this limitation, muscle afferent activity may be useful for motion feedback if the movement to be controlled is within a narrow joint range such as postural sway.

Kostov, A, Sinkjaer, T, & Upshaw, B, 1996: Gait Event Discrimination Using ALNs for Control of FES in Foot-Drop Problem, Proc. 18th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 1:459-460.

Discrimination of stance and swing phases of the gait is required for control of functional electrical stimulation (FES) used to assist with ankle dorsiflexion in foot-drop problem. Simple thresholds applied to a human whole nerve signal processed using a sophisticated digital signal processing technique did not result in a safe and reliable control method. In this preliminary study, the authors use the same sensory signals to evaluate a gait event discriminator (GED), based on Adaptive Logic Networks (ALNs). The evaluation was performed off-line using neural signals for sensory feedback and a signal from a heel switch as the output to the stimulator. The neural signal was recorded using a cuff electrode implanted around the calcaneal nerve in the left leg of a male subject and the heel switch was installed inside the shoe of the same leg. Preliminary results suggest that ALNs can discriminate precise timing of heel contact and heel lift during FES-assisted walking. Restriction rules based on a priori knowledge were used to verify decisions made by ALNs and to eliminate infrequent functional errors providing maximum safety for the subject.

Malek, A M, & Mark, R G, 1989: Functional Electrical Stimulation of the Latissimus Dorsi Muscle for Use in Cardiac Assist, IEEE Trans. Biomed. Eng., 36(7):781-788.

Direct and nondirect nerve stimulation modes of the thoraco-dorsal nerve leading to the latissimus dorsi muscle (LDM) were evaluated by using nerve cuff electrodes (NCEs) and intramuscular electrodes (IMEs), respectively. Following electrode implantation, the LDM was chronically stimulated for two months to induce muscle transformation to oxidative, fatigue-resistant type I muscle fibers. Threshold and impedance values were measured regularly to establish the stability of the implants. The LDM was then dissected, shaped into a ventricle, subjected to a hydraulic load and stimulated using a controlled-voltage pulse-train stimulator with adjustable parameters. Electrical input and hydraulic output variables were measured to obtain the recruitment characteristics and to compare the efficiencies of the two types of electrodes. Results indicate a tradeoff between the NCE's lower threshold, higher recruitment, and lower energy consumption at saturation, and the IME's greater mechanical stability and better long- term reproducibility.

Mosallaie, K, Riso, R R, & Sinkjaer, T, 1996: Muscle Afferent Activity Recorded During Passive Extension-Flexion of Rabbit's Foot, Proc. 18th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 4:1488-1489.

In this investigation the authors studied the recorded neural activities from muscle afferents regarding ankle joint kinesthesia using cuff electrodes in a reduced rabbit model of human peripheral nerves. The ankle was passively rotated in an extension-flexion plane while the neural activity was recorded from tibial and peroneal nerves. The recorded signals mainly reflected a mixture of activity from primary and secondary muscle afferents. The activity from either nerves increased when the corresponding muscle group is stretched, an abrupt decrease in activity occurred when the muscles were shortened. The evoked activity was dependent on the initial joint position and velocity of ankle rotation.

Popovic, D B, Stein, R B, Jovanovic, K L, Dai, R, Kostov, A, & Armstrong, W W, 1993: Sensory Nerve Recording for Closed-Loop Control to Restore Motor Functions, IEEE Trans. Biomed. Eng., 40(10):1024-1031.

A method is developed for using neural recordings to control functional electrical stimulation (FES) to nerves and muscles. Experiments were done in chronic cats with a goal of designing a rule-based controller to generate rhythmic movements of the ankle joint during treadmill locomotion. Neural signals from the tibial and superficial peroneal nerves were recorded with cuff electrodes and processed simultaneously with muscular signals from ankle flexors and extensors in the cat's hind limb. Cuff electrodes are an effective method for long-term chronic recording in peripheral nerves without causing discomfort or damage to the nerve. For real-time operation the authors designed a low- noise amplifier with a blanking circuit to minimize stimulation artifacts. They used threshold detection to design a simple rule-based control and compared its output to the pattern determined using adaptive neural networks. Both the threshold detection and adaptive networks are robust enough to accommodate the variability in neural recordings. The adaptive logic network used for this study is effective in mapping transfer functions and therefore applicable for determination of gait invariants to be used for closed loop control in an FES system. Simple rule-bases will probably be chosen for initial applications to human patients. However, more complex FES applications require more complex rule-bases and better mapping of continuous neural recordings and muscular activity. Adaptive neural networks have promise for these more complex applications.

Qi, H, Tyler, D J, & Durand, D M, 1999: Neurofuzzy Adaptive Controlling of Selective Stimulation for FES: A Case Study, IEEE Trans. Rehab. Eng., 7(2):183-192.

A controller was designed for the selective stimulation of the sciatic nerve with a multiple contact cuff electrode to generate a desired torque in the ankle joint of cat. The design integrates three approaches, artificial neural network (ANN) modeling, fuzzy logical adaptation, and geometrical mapping. The geometrical mapping refers to the vector transformation from the joint coordinates to the virtual muscle coordinates which have been conceptually developed to represent the major recruitment features of contact-based functional units in the physical plant. This method reduces the complexity of generating a data set for training the neural network in the feedforward path and implementing the on-line learning algorithm embedded in the feedback loop. The controller was evaluated by computer simulation with the experimental data obtained from the torque generation in five acute cats. The results show that the ANN-based feedforward is capable of predicting 65% of a given desired isometric torque, and the fuzzy logical machine is able to provide suitable gains for feedback modulation to reduce the error from 35 to 8.5% and produce a robust control.

Rijkhoff, N J M, Holsheimer, J, Koldewijn, E L, Struijk, J J, van Kerrebroeck, P E V, Debruyne, F M J, & Wijkstra, H, 1994: Selective Stimulation of Sacral Nerve Roots for Bladder Control: a Study by Computer Modeling, IEEE Trans. Biomed. Eng., 41(5):413-424.

The aim of this study was to investigate theoretically the conditions for the activation of the detrusor muscle without activation of the urethral sphincter and afferent fibers, when stimulating the related sacral roots, Therefore, the sensitivity of excitation and blocking thresholds of nerve fibers within a sacral root to geometric and electrical parameters in tripolar stimulation using a cuff electrode, have been simulated by a computer model. A 3D rotationally symmetrical model, representing the geometry and electrical conductivity of a nerve root surrounded by cerebrospinal fluid and a cuff was used, in combination with a model representing the electrical properties of a myelinated nerve fiber. The electric behavior of nerve fibers having different diameters and positions in a sacral root was analyzed and the optimal geometric and electrical parameters to be used for sacral root stimulation were determined. The model predicts that an asymmetrical tripolar cuff can generate unidirectional action potentials in small nerve fibers. While blocking the large fibers bidirectionally. This result shows that selective activation of the detrusor may be possible without activation of the urethral sphincter and the afferent fibers.

Riso, R R, Mosallaie, F K, Jensen, W, & Sinkjaer, T, 2000: Nerve Cuff Recordings of Muscle Afferent Activity From Tibial and Peroneal Nerves in Rabbit During Passive Ankle Motion, IEEE Trans. Rehab. Eng., 8(2):244-258.

Activity from muscle afferents regarding ankle kinesthesia was recorded using cuff electrodes in a rabbit preparation in which tactile input from the foot was eliminated. The purpose was to determine if such activity can provide information useful in controlling functional electrical stimulation (FES) systems that restore mobility in spinal injured man. The rabbit's ankle was passively flexed and extended while the activity of the tibial and peroneal nerves was recorded. Responses to trapezoidal stimulus profiles were investigated for excursions from 100 to 600 using velocities from 50/s to 300/s and different initial ankle positions. The recorded signals mainly reflect activity from primary and secondary muscle afferents. Dorsiflexion stretched the ankle extensors and produced velocity dependent activity in the tibial nerve, and this diminished to a tonic level during the stimulus plateau. The peroneal nerve was silent during dorsiflexion, but was activated by stretch of the peroneal muscles during ankle extension. The responses of the two nerves behaved in a reciprocal manner, hut exhibited considerable hysteresis, since motion that relaxed the stretch to the driving muscle produced an immediate cessation of the prior stretch induced activity. A noted difference between the tibial and peroneal nerve responses is that the range of joint position change that activated the flexor afferents was greater then for the extensor afferents. Ankle rotation at higher velocities increased the dynamic stretch evoked responses during the stimulus ramp but showed no effect on the tonic activity during the stimulus plateau. Prestretching the muscles by altering the initial position increased the response to the ramp movement, however, for the peroneal nerve, when the prestretch brought the flexor muscles near to their maximal lengths, the response to additional stretch provided by the ramp movement was diminished. The results indicate that the whole nerve recorded muscle afferent activity may be useful for control of FES assisted standing, because it can indicate the direction of rotation of the passively moved ankle joint, along with coarse information regarding the rate of movement and static joint position.

Rozman, J, & Tekavcic, I, 1996: Selective Stimulation of a Peripheral Nerve: Correction of Drop Foot in Three Patients, Proc. 18th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 5:2256-2257.

We present an evaluation of an implantable system with a monopolar half-cuff for selective stimulation of the common peroneal nerve in three hemiplegic patients. The stimulus proposed in this work for effecting selective stimulation of the superficial region of the human common peroneal nerve in more physiological order were current, charge balanced, and biphasic pulses with a rectangular cathodic component, and exponential decay anodic component delayed for 50 µs. Results show that a half-cuff electrode is capable of making a long term selective activation, mainly of those muscles that contribute to strong dorsal flexion and moderate eversion of the hemiplegic's foot. Moreover, significant improvements of gait dynamics without excessive eversion were observed.

Sahin, M, & Durand, D M, 1998: Closed-Loop Stimulations of Hypoglossal Nerve Using Its Spontaneous Activity as the Feedback Signal, Proc. 20th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 5:2524-2527.

Electrical recruitment of the upper airway (UAW) muscles has been attempted as a treatment method for Obstructive Sleep Apnea (OSA). Hypoglossal nerve (HG) and genioglossus muscle (GG) stimulations have given successful results in OSA patients. A reliable method for detection of obstructions is needed to trigger the stimulations in phase with respiration during obstructive breaths before this technique can be used clinically. Here, the authors investigate the possibility of closed-loop HG nerve stimulations using its spontaneous activity for detection of obstructions in a dog model. The activity of the HG nerve is recorded with chronically implanted nerve cuff electrodes in sleeping dogs while a force is being applied onto the submental region to collapse the airways. The increase in the phasic HG activity as a response to the submental force is used to trigger the stimulations. Closed-loop stimulations are shown to relieve the UAWs from the collapsing effect of the submental force.

Sepulveda, F, Jensen, W, & Sinkjaer, T, 2001: Using Nerve Signals From Muscle Afferent Electrodes to Control FES-Based Ankle Motion in a Rabbit, Proc. 23rd Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 2:1290-1292.

Electroneurographic (ENG) signals were extracted from muscle afferent fibers and used for real-time closed-loop control of FES-based ankle movements in a rabbit preparation. For extraction of the ENG signals, tripolar cuff electrodes were implanted onto the peroneal and tibial nerves in the left hind limb. A neural network was used for extraction of joint angles from the recorded ENGs. For stimulation purposes, percutaneous stainless steel wires were placed intramuscularly into the tibialis anterior and lateral gastrocnemius muscles, respectively. Stimulation intensity was varied by changing the applied pulse width (PW). Step and sinusoidal tracking tasks were performed using a standard PID controller. Results showed that the system's performance is highly sensitive to the initial joint angle. Further, angles estimated from the ENG (by the neural network) lost correlation with measured angles as a given experiment progressed. Improvements were seen when the neural network was allowed to learn intermittently during an experimental session. Finally, a standard PID controller required frequent retuning during an experimental session, which, not surprisingly, suggests that an adaptive controller should be used.

Singh, K, Richmond, F J R, & Loeb, G E, 1999: Muscle Recruitment by Intramuscular vs. Nerve Cuff Electrical Stimulation, Proc. First Joint BMES/EMBS Conf. 1:593.

Functionally useful reanimation of paralyzed limbs depends on achieving reliable fine- control of muscle recruitment and force. We have used force and EMG recordings and histochemical analysis to investigate the recruitment properties of intramuscular (IM) and nerve cuff (NC) electrodes implanted acutely or chronically in cat hindlimbs, focusing an stimulation intensities and frequencies of interest for functional electrical stimulation (FES). NC stimulation produced very steep and surprisingly unstable recruitment, mostly of the fast-fatiguable (FF) motor units (MUs). IM stimulation produced more gradual, reliable and less fatigable recruitment of a mix of MUs that tended to be localized in neuromuscular compartments.

Sinkjaer, T, & Popovic, D, 2003: Peripheral Nerve Stimulation in Neurological Rehabilitation, Proc. First Int'l IEEE EMBS Conf. Neur. Eng., 474-476.

An injury to the central nervous system can result in a permanent loss of the voluntary motor function and sensation. However, the peripheral motor and sensory nerves below the level of lesion often remain intact, and so do the muscles. Functional Electrical Stimulation (FES) is a technique to restore motor and sensory functions after such injuries. The forces generated in muscles activated by FES can be graded by varying the stimulus pulses, but the relationship of the force to the stimulus pulse varies in a complex manner that depends on, for example, muscle length, electrode-nerve coupling, and activation history. Several studies have shown that the application of closed-loop control techniques can improve the regulation of the muscle activation. Natural sensors such as those found in the skin, muscles, tendons, and joints present an attractive alternative to artificial sensors for FES purposes because they are present throughout the body and contain information useful for feedback control. Moreover, the peripheral sensory apparatus is still viable after brain and spinal cord injuries. Electrical signals can be recorded using long-term implanted nerve cuff electrodes in the human peripheral nerves. Reliable detection of sensory nerve signals is essential if such signals are to be of use in sensory-based functional electrical stimulation neural prosthetics as a replacement for artificial sensory (switches, strain gauges, etc.) In this paper the signal characteristics of the sensors, the nerve interface, signal processing, and example of human applications to restore motor functions are described. In the second part of this presentation, stimulation of sensory nerves in CNS injured persons to improve their motor functions through neurorehabilitation will be addressed.

Implantable Systems

Boyer, S, Sawan, M, Abdel-Gawad, M, Robin, S, & Elhilali, M M, 2000: Implantable Selective Stimulator to Improve Bladder Voiding: Design and Chronic Experiments in Dogs, IEEE Trans. Rehab. Eng., 8(4):464-470.

Among the treatments to enhance the bladder voiding, the sacral roots neurostimulation is one of the most promising techniques. The electrostimulation of sacral nerves provokes a simultaneous contraction of the detrusor muscle as well as the external urethral sphincter (EUS). A new simplified-architecture implantable stimulator with its wireless controller have been designed to investigate high-frequency inhibition stimulation strategies. This innovative technique based on high-frequency inhibition reduces sphincter activity during stimulation. Low-frequency current pulses also applied to the sacral roots induces contraction of the detrusor muscle resulting in low pressure voiding. Chronic experiments were carried out on ten male mongrel paraplegic dogs. One cuff electrode was implanted along with each stimulator for eight months. The animals were stimulated twice a day using the prototypes of the authors' implantable selective stimulator while voided and residual urine volume were measured during the procedure. These experiments revealed that the proposed stimulation strategy enhances bladder voiding by more than 50% in comparison with low-frequency only stimulation. The residual urine volume was reduced to an average of 9% and low pressure micturition was achieved as shown by weekly cystourethrogram.

Chien, C-N, & Jaw, F-S, 2005: Miniature Telemetry System for the Recording of Action and Field Potentials, J. Neuroscience Methods, 147(1):68-73.

A simple miniature telemetry system for neural recording from freely moving rats is described. It weighs only 1% of the body weight of an adult rat and its recordings are devoid of artifacts due to the animal movement. Together with its long recording time (more than 38 h), its isotropic nature, which is essential for working with freely moving animals, offers further advantages. A frequency-modulation receiver with a flat frequency response down to 6 Hz has been designed for wide-spectrum recording of neural signals, allowing field potential recordings. A detailed printed-circuit layout and the lack of a trimming requirement will allow the system to be easily duplicated by other neuroscientists who are not familiar with wireless-transmission technologies.

Dennis, R G, Dowb, D E, & Faulkner, J A, 2003: An Implantable Device for Stimulation of Denervated Muscles in Rats, Med. Eng. & Physics, 25(3):pp 239-253.

The purposes of the present study were (1) to develop an implantable device capable of being pre-programmed to generate a protocol of chronic contractions in denervated hind-limb muscles of rats, and (2) to verify the design by implanting the stimulators for five weeks in rats to identify a protocol of stimulation that maintains muscle mass and maximum force in stimulated-denervated extensor digitorum longus (EDL) muscles. This implantable stimulator system did not hinder animal movement or hygiene, and enabled the animals to be housed in regular animal facilities, since neither external equipment nor an externally generated magnetic field was required. The pre- programmable microcontroller allows detailed basic research into the cellular and tissue response to different stimulation protocols. The micropower design of the battery powered device enabled chronic stimulation of denervated EDL muscles for the five weeks of this initial study. Stimulation protocols of 9-11 V pulse amplitude, 0.4 ms bipolar pulse width, 100 Hz, 20 pulses per contraction, and 100 or 300 contractions generated per day maintained muscle mass and maximum force in denervated EDL muscles of rats at values near control values for innervated muscles.

Lee, S-Y, Lee, S-C, & Chen, J-J J, 2003: VLSI Implementation of Wireless Power and Data Transmission Circuits for Micro-Stimulator, Int'l Symp. VLSI Technology, Sys., & Applications, 164-167.

This paper presents the realization of the radio frequency (RF) power and data transmission for implantable micro-stimulators. This implantable device includes an internal RF front-end circuit, a control circuit, and a stimulator. A 2MHz AM modulated signal including the power and data necessary for the implantable device is received, and a stable DC voltage and digital data will be extracted to stimulate the neuromuscular stimulation. The stimulator is a current-source stimulator, which is capable to generate a wide range of stimulation waveforms and stimulation patterns for a nerve cuff electrode. In this paper, most of the integrated circuits for the implantable device have been proposed and verified by using Hspice according to the technology of TSMC 0.25 µm CMOS process.

Gudnason, G, Bruun, E, & Haugland, M, 1999: An Implantable Mixed Analog/Digital Neural Stimulator Circuit, Proc. 1999 IEEE Int'l Symp. Circuits & Sys., 5:375-378.

This paper describes a chip for a multichannel neural stimulator for functional electrical stimulation. The chip performs all the signal processing required in an implanted neural stimulator. The power and signal transmission to the stimulator is carried out via an inductive link. From the signals transmitted to the stimulator, the chip is able to generate charge-balanced current pulses with a controllable length and amplitude for stimulation of nerve fibres. The chip has 4 output channels so that it can be employed in a cuff electrode with multiple connections to a nerve. The purpose of the functional electrical stimulation is to restore various bodily functions (e.g. motor functions) in patients who have lost them due to injury or disease.

Manwaring, M L, Jones, K L, & Manwaring, K H, 1996: Issues in Developing a Communication Protocol for Wireless (Implanted) Biodevices, Proc. Ninth IEEE Symp. Computer-Based Med. Sys., 65-70.

Describes current research in the development of subcutaneously implanted biological sensor devices (biodevices). In particular, the matter presented here is the issue of developing a safe digital communication protocol for communicating through a wireless link between a data interrogator and an implanted system.

Peng, C-W, Chen, J-J J, Lin, C-C K, Poon, P W-F, Liang, C-K, & Lin, K-P, 2004: High Frequency Block of Selected Axons Using an Implantable Microstimulator, J. Neuroscience Methods, 134(1):81-90.

Currently, the majority of neural stimulation studies are limited to acute animal experiments due to lack of suitable implantable microstimulation devices. As an initial step to observe the long-term effects of neural stimulation, a system consisting of an external wireless controller and an implantable dual-channel microcontroller-based microstimulator for tripolar high frequency blocking was developed. The system is not only small in size, and thus suitable for short-term implantation, but also has sufficient current output parameter ranges to meet the demand for high frequency blocking experiments. Using this implantable microstimulator, a series of experiments were conducted on New Zealand rabbit's tibial nerve, including frequency and amplitude selection in driving stimulus and blocking effect tests, which were designed to assess the feasibility and efficiency of the device via torque measurements. Our results showed that the implantable microstimulator system gave a satisfactory performance and could be utilized to achieve selective stimulation and blocking on various sizes of nerve fibers. Our implantable microstimulation system is not only a novel tool for neuromuscular control studies but could also provide a basis for developing various types of sophisticated neural prostheses.

Sun, M, Li, D L, Zhao, J, Roche, P A, Wessel, B L, & Sclabassi, R J, 2005: Biological Resources Within the Human Body Can Be Used to Operate Neural Implants, Proc. First Int'l Conf. Neur. Interface & Control, 6-9.

Implantable neural devices have many therapeutic, diagnostic and prosthetic applications. Although there have been exciting developments in constructing these devices, two critical problems, data communication between the implanted device and external computers as well as electrical power to the device, have not yet been solved. We investigate these problems using the volume conduction properties of the human body. A prototype implantable device is constructed equipped with a volume conduction data communication channel. A new power delivery antenna is conceptualized, inspired by the power delivery mechanisms of electric fish. Our investigation indicates that the volume conduction resources within the human body may provide a powerful solution to both problems.

von Arx, J A, & Najafi, K, 1999: A Wireless Single-Chip Telemetry-Powered Neural Stimulation System, IEEE Int'l Solid-State Circuits Conf., 214-215.

This fully-integrated single-chip inductively-powered microsystem is capable of providing milliwatts for wireless operation. The chip is for an implantable multichannel neural microstimulator, but can be also used in other emerging applications for sensing and actuation microsystems. The fully-integrated neuromuscular electrical stimulation system (FINESS) is for use in peripheral nerve stimulation and will be attached to cuff electrodes that interface to the nerve for delivery of a bi-phasic stimulation pulse. FINESS receives all power and data through inductive coupling with an integrated, on-chip coil.

Wise, K D, Anderson, D J, Hetke, J F, Kipke, D R, & Najafi, K, 2004: Wireless Implantable Microsystems: High-Density Electronic Interfaces to the Nervous System, Proc. IEEE, 92(1):76-97.

This paper describes the development of a high-density electronic interface to the central nervous system. Silicon micromachined electrode arrays now permit the long- term monitoring of neural activity in vivo as well as the insertion of electronic signals into neural networks at the cellular level. Efforts to understand and engineer the biology of the implant/tissue interface are also underway. These electrode arrays are facilitating significant advances in our understanding of the nervous system, and merged with on-chip circuitry, signal processing, microfluidics, and wireless interfaces, they are forming the basis for a family of neural prostheses for the possible treatment of disorders such as blindness, deafness, paralysis, severe epilepsy, and Parkinson's disease.

Ziaie, B, Nardin, M D, Coghlan, A R, & Najafi, K, 1997: A Single-Channel Implantable Microstimulator for Functional Neuromuscular Stimulation, IEEE Trans. Biomed. Eng., 44,(10):909-920.

The single-channel implantable microstimulator device measures 2×2×10 mm3 and can be inserted into paralyzed muscle groups by expulsion from a hypodermic needle. Power and data to the device are supplied from outside by RF telemetry using an amplitude-modulated 2-MHz RF carrier generated using a high-efficiency class-E transmitter. The transmitted signal carries a 5-b address which selects one of the 32 possible microstimulators. The selected device then delivers up to 2 µC of charge stored in a tantalum chip capacitor for up to 200 µs (10 mA) into loads of <800 O through a high-current thin-film iridium-oxide (IrOx) electrode (~0.3 mm2 in area). A bi-CMOS receiver circuitry is used to: generate two regulated voltage supplies (4.5 and 9 V), recover a 2-MHz clock from the carrier, demodulate the address code, and activate the output current delivery circuitry upon the reception of an external command. The overall power dissipation of the receiver circuitry is 45-55 mW. The implant is hermetically packaged using a custom-made glass capsule.

Implants - Packaging and Interconnect

Meyer, J-U, Stieglietz, T, Scholz, O, Haberer, W, & Beutel, H J, 2001: High Density Interconnects and Flexible Hybrid Assemblies for Active Biomedical Implants, IEEE Trans. Advanced Packaging, 24(3):366-374.

Advanced microtechnologies offer new opportunities for the development of active implants that go beyond the design of pacemakers and cochlea implants. Examples of future implants include neural and muscular stimulators, implantable drug delivery systems, intracorporal monitoring devices and body fluid control systems. The active microimplants demand a high degree of device miniaturization without compromising on design flexibility and biocompatibility requirements. With the need for integrating various microcomponents for a complex retina stimulator device, we have developed a novel technique for microassembly and high-density interconnects employing flexible, ultra-thin polymer based substrates. Pads for interconnections, conductive lines, and microelectrodes were embedded into the polyimide substrate as thin films. Photolithography and sputtering has been employed to pattern the microstructures. The novel "MicroFlex interconnection (MFI)" technology was developed to achieve chip size package (CSP) dimensions without the requirement of using bumped flip chips (FC). The MFI is based on a rivet like approach that yields an electrical and mechanical contact between the pads on the flexible polyimide substrate and the bare chips or electronic components. Center to center bond pad distances smaller than 100 µm were accomplished. The ultra thin substrates and the MFI technology was proven to be biocompatible. Electrical and mechanical tests confirmed that interconnects and assembly of bare chips are reliable and durable. Based on our experience with the retina stimulator implant, we defined design rules regarding the flexible substrate, the bond pads, and the embedded conductive tracks. It is concluded that the MFI opens new venues for a novel generation of active implants with advanced sensing, actuation, and signal processing properties.

Stieglitz, T, 2002: Polymer-Based Substrates and Flexible Hybrid Assembly Techniques for Implantable Active Microdevices, IEEE Trans. Biomed. Eng., 35(5):323-327.

The size of the transducers for neural stimulation has shrunk steadily with application of thin-film techniques to electrode design. The feasibility is examined of designing millimeter- and submillimeter-sized power sources based on RF coupling that could be integrated into these implants to provide power without a tethering power cable. The coupling between a transmitter coil and receiver coil when the coil diameters are markedly different is analyzed, and for these circumstances, a simple Thevenin equivalent model is developed to describe the power transmission between the transmitter and receiver. The equivalent circuit developed gives insight into the way that coil diameters, frequency, and turns affect coupling between large and small coils. Several examples demonstrate that milliwatt range power sources can be implemented with millimeter- and submillimeter-diameter receivers.

Implants - Power and Communications

Liang, C-K, Chen, J-J J, Chung, C-L, Cheng, C-L, & Wang, C-C, 2005: An Implantable Bi-Directional Wireless Transmission System for Transcutaneous Biological Signal Recording, Physiol. Meas., 26:83-97.

A PSK-demodulator for a bi-directional data transmission in passive telemetric microsystems is presented in this work. These systems, which use the telemetry link for energy and data transmission, are based on identification systems, which use ASK- modulation for both data transfer directions. This leads to problems with a bi-directional data transmission in sensor applications, where the power consumption is significantly higher than in identification systems. A system that uses a PSK to transfer data into the microsystem to improve the energy transfer during data transmission is presented. The key component of this system is a novel PSK-demodulator, which works without an internal oscillator and therefore no PLL is needed. The major advantages of the presented system are the self-adaptation to the carrier frequency and the independence of the demodulator of parameter drifts.

Tang, Z, Smith, B, Schild, J H, & Peckham, P H, 1995: Data Transmission From an Implantable Biotelemeter by Load-Shift Keying Using Circuit Configuration Modulator, IEEE Trans. Biomed. Eng., 42(5):524-528.

Using the reflected impedance property of an inductive couple (transformer), a modulation method, load-shift keying using circuit configuration modulator (LSK-CCM), was developed to perform data transmission from an implantable telemeter. With a very simple circuit, this method utilizes a radio-frequency electromagnetic field induced with a single pair of coils to transmit power into the implant and data out of it.

Troyk, P R, & Schwan, M A K, 1992: Closed-Loop Class E Transcutaneous Power and Data Link for Microimplants, IEEE Trans. Biomed. Eng., 39(6):589-599.

The use of a multifrequency transmitter coil driver based on the class E topology is described. The development of a high-Q approximation, which simplifies the design procedure is presented. A closed-loop controller to compensate for transmitter and receiver variations, and a method of data modulation using synchronous frequency shifting are described. The closed-loop class E circuit shows great promise, especially for circuits with unusually low coefficients of coupling. Currents of several amperes, at radio frequencies, can easily and efficiently be obtained.

Yu, H, & Najafi, K, 2001: Circuitry for a Wireless Microsystem for Neural Recording Microprobes, Proc. 23rd Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 1:761-764.

Integrated circuits for use in a wireless microsystem used in neural recording are described. The implantable microsystem will be powered and transmit digitized data using RF telemetry. Recorded neural signals are amplified, multiplexed, digitized using a 2/sup nd/ order sigma-delta modulator, and then transmitted to the outside world by an on-chip transmitter. The circuit is designed using a standard 1.5 /spl mu/m CMOS process. Several circuit blocks have been designed, fabricated and show to operate as expected.

Ziaie, B, Rose, S C, Nardin, M D, & Najafi, K, 2001: A Self-Oscillating Detuning-Insensitive Class-E Transmitter for Implantable Microsystems, IEEE Trans. Biomed. Eng., 48(3):397-400.

Describes a low-cost, self-oscillating, detuning-insensitive, class-E driver for transcutaneous power and data transmission to implantable microsystems. A voltage feedback scheme using a fast comparator for zero-crossing detection and a CMOS start- up circuit were used to stabilize the class-E operation for various transmitter coil inductance values. This technique solves the common problem of mismatch between the switching frequency of the driving device and the resonant frequency of the load network, which can cause excessive power loss and damage to the active device. Data is transmitted by AM modulation of the carrier through switching the power supply between two levels. The transmitter uses a 9-V supply consumes 212 mA, operates at 3.9 MHz, and has an efficiency of 71%. The efficiency is stable (<2% change) against 13% variations in the inductance value of a pancake shaped transmitter coil.

Zierhofer, C M, & Hochmair, E S, 1996: Geometric Approach for Coupling Enhancement of Magnetically Coupled Coils, IEEE Trans. Biomed. Eng., 43(7):708-714.

This paper presents a geometric approach for the enhancement of the coupling coefficient between two magnetically coupled coils. It is demonstrated that the coupling coefficient can be considerably enhanced, if the turns of the coils are not concentrated at the circumferences, but distributed across the diameters. For analysis, each of the two coils is assumed to be composed of concentric circular loops. The experimental results are in very good agreement with the theoretical results.

Zierhofer, C M, & Hochmair, E S, 1992: The Class-E Concept for Efficient Wide-Band Coupling-Insensitive Transdermal Power and Data Transfer, Proc. 14th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 2:382-383.

This paper presents an innovative method for the transcutaneous transmission of RF power and digital data via an inductive link. The system is based on the single ended class-E power amplification scheme. A self oscillating class-E tuned power amplifier involving an inductive link permits high-efficiency coupling-insensitive power transmission. The oscillation frequency is not fixed but influenced by the coupling of the coils. Due to the excellent switching characteristics of the oscillator, Amplitude Shift Keying (ASK) may be employed for digital data transmission. Data decoding can easily be achieved by envelope detection. The realization of the system requires a small number of circuit components. It is employed for the transcutaneous transmission of digital data and power in a Cochlear Prosthesis system.

Zierhofer, C M, & Hochmair, E S, 1990: High-Efficiency Coupling-Insensitive Transcutaneous Power and Data Transmission Via an Inductive Link, IEEE Trans. Biomed. Eng., 37(7): 716-722.

A new approach is presented for transmitting RF power and signal via an inductive link. Such an approach optimizes the power efficiency of the overall transmission scheme comprising the power amplifier plus the inductive link. Power amplification is based on the single ended class E concept. The power amplification stage is self-oscillating, and thus the oscillation frequency is influenced by the coupling of the coils. The resulting operating frequency offset yields improved power transmission performance of the circuit, since the oscillation frequency tracks the absolute transmission efficiency maximum. A detailed analysis is given. Realization of the approach requires a minimal number of circuit components. Experimental and theoretical results are in good agreement.

Non-Implantable Systems

Cheever, E A, Birge, J R, Thompson, D R, Santamore, W P, & George, D T, 1995: A Microprocessor-Based Multi-Channel Muscle Stimulator for Skeletal Muscle Cardiac Assist, IEEE 17th Annual Conf. Eng. in Med. & Biol. Soc., 1:147-148.

Describes a portable, multichannel skeletal muscle stimulator developed for use in research in skeletal muscle cardiac assist (SMCA). The primary features of the stimulator are that it allows selective stimulation through multiple nerve-cuff electrodes and that arbitrary voltage patterns can be delivered to each electrode. The electrodes are electrically isolated from one another to effect regional (selective) stimulation. Selective stimulation offers greater control over the spatial pattern of muscle stimulation and may allow for increased muscle efficiency during skeletal muscle cardiac assist.

Neuroelectric Control Systems

Wolpert, S, Osborn, M J, Neill, O, & M, A, 1994: A VLSI-Based System for Localization of Extracellular Potentials, Proc. 16th Annual Int'l Conf. IEEE Eng. in Med. & Biol. Soc., 2:972-973.

An interface between a biological nerve fiber and an arbitrary electromechanical device was implemented using an analog VLSI-based amplifier/filter circuit. A silastic cuff was fitted over a live nerve bundle, and an electrode of Teflon coated silver wire was used to sense extracellular potentials. A dedicated CMOS VLSI-based circuit then filtered and amplified those signals to an amplitude appropriate for triggering an arbitrary circuit such as the four-phase stepper motor used in this study. In circuit tests, the amplifier/filter circuit was capable of sensing signals as low as 50 microvolts in an in vitro preparation of the optic nerve of Limulus polyphemus, and effect rotation of the four-phase stepper motor with detected impulses. Using a silastic cuff electrode and dedicated VLSI circuitry for compactness and reliability, this circuit has excellent long term potential as a component of a surgically implanted system. It is also a pivotal first step in the implementation of a comprehensive cybernetic interface.

Chronic Implants in the Mouse (Mus Musculus)

Carp, J S, Tennissen, A M, Chen, X Y, Schalk, G, & Wolpaw, J R, 2005: Long-Term Spinal Reflex Studies in Awake Behaving Mice, J. Neuroscience Methods, in press.

The increasing availability of genetic variants of mice has facilitated studies of the roles of specific molecules in specific behaviors. The contributions of such studies could be strengthened and extended by correlation with detailed information on the patterns of motor commands throughout the course of specific behaviors in freely moving animals. Previously reported methodologies for long-term recording of electromyographic activity (EMG) in mice using implanted electrodes were designed for intermittent, but not continuous operation. This report describes the fabrication, implantation, and utilization of fine wire electrodes for continuous long-term recordings of spontaneous and nerve- evoked EMG in mice. Six mice were implanted with a tibial nerve cuff electrode and EMG electrodes in soleus and gastrocnemius muscles. Wires exited through a skin button and traveled through an armored cable to an electrical commutator. In mice implanted for 59-144 days, ongoing EMG was monitored continuously (i.e., 24 h/day, 7 days/week) by computer for 18-92 days (total intermittent recording for 25-130 days). When the ongoing EMG criteria were met, the computer applied the nerve stimulus, recorded the evoked EMG response, and determined the size of the M-response (MR) and the H-reflex (HR). It continually adjusted stimulation intensity to maintain a stable MR size. Stable recordings of ongoing EMG, MR, and HR were obtained typically 3 weeks after implantation. This study demonstrates the feasibility of long-term continuous EMG recordings in mice for addressing a variety of neurophysiological and behavioral issues.

Weiergräber, M, Henry, M, Hescheler, J, Smyth, N, & Schneider, T, 2005: Electrocorticographic and Deep Intracerebral EEG Recording in Mice Using a Telemetry System, Brain Res. Protocols, 14(3):154-164.

Telemetric EEG recording plays a crucial role in the neurological characterization of various transgenic mouse models giving valuable information about epilepsies and sleep disorders in humans. In the past different experimental approaches have been described using tethered systems and jacket systems containing recorders. A main disadvantage of these is their sometimes unphysiological, restraining character. Telemetric EEG recording overcomes most of these disadvantages and allows precise and highly sensitive measurement under various physiological and pathophysiological conditions and different stages of consciousness, as during seizure activity and different sleep stages. Here we present the first contiguous, detailed description of a successful and quick technique for intraperitoneal implantation or subcutaneous pouch implantation of a radiofrequency transmitter in mice and subsequent lead placement in both epidural and deep intracerebral position. Preoperative preparation of the mice, suitable anesthesia, as well as postoperative treatment including pain management are described in detail to provide optimal postoperative recovery. Finally, we display examples of electrocorticograms and deep intracerebral recordings, present strategies to maximize signal-to-noise ratio, paying special attention to major pitfalls and possible artefacts occurring in telemetric EEG recording in mice.

Chronic Implants in the Rat (Rattus Norvegicus)

Shimatani, Y, Grabauskiene, S, & Bradley, R M, 2002: Long-Term Recording From the Chorda Tympani Nerve in Rats, Physiol. & Behavior, 76(1):143-149.

Cuff electrodes with headcap connectors were implanted around the rat chorda tympani nerve. Whole nerve recordings under anesthesia were made from these nerves every week to chemical, thermal and tactile stimuli applied to the anterior tongue. The signal/noise ratio of these recordings was similar to acute recordings from the chorda tympani nerve, and the nerves were spontaneously active. Responses to chemical as well as thermal and mechanical stimulation of the tongue were recorded as early as 2 and 3 weeks after implantation and recordings from the same nerve were made for more than 3 months. These results have demonstrated the feasibility of making long- term chronic recordings of chemosensory activity in the chorda tympani nerve. The cuff electrode has great potential to provide correlative information between neurophysiological and behavioral data.

Sigma-Delta Modulation

Zierhofer, C M, 1996: A Multiplier-Free Digital Sinusoid Generator Based on Sigma-Delta Modulation, IEEE Trans. Circuits & Sys. Ii: Analog & Digital Signal Processing, 43(5):387-396.

In this paper sigma-delta (S-D) sequences derived from a single-loop numeric S-D modulator with sinusoidal input are investigated, A class of limit cycles shows a special kind of symmetry, designated as "half-symmetry". It is shown that half-symmetric S-D sequences are especially suited for automatic generation by means of an autonomous oscillator. The design of such an oscillator is presented. The central part is a single-loop numeric S-D modulator. The two-level output sequence of the S-D modulator is accumulated in lossless discrete integrators and fed back to the input. If the initial conditions of the oscillator registers are chosen properly in relation to a system constant F, the oscillator generates a two-level S-D sequence identical to the sequence of a S-D modulator which is externally driven by a pure sinusoid. Conditions for system constant F and initialization for periodic operation are derived, If constant F is an integer, the operation of the oscillator is exclusively based on integers. Thus, although the network is highly recursive, truncation- or roundoff errors are avoided and problems with respect to stability do not occur.

Zierhofer, C M, 2000: Adaptive Sigma-Delta Modulation with One-Bit Quantization, IEEE Trans. Circuits & Sys. II: Analog & Digital Signal Processing, 47(5):408-415.

A method for improving the signal-to-noise ratio (SNR) of sigma-delta modulators with one-bit quantization is presented. The two-level feedback signal of a standard sigma- delta modulator is replaced by a multilevel signal, which is a superposition of two parts. One part s(n) represents a rough estimate of the instantaneous amplitude of the input signal (prediction signal), and the other yb(n) is the sign of the quantizer output, multiplied with constant b. Compared to a nonadaptive modulator, the amplitude of yb(n) is reduced. Therefore, less noise power is introduced in the quantizer, and the SNR is considerably enhanced. Signal s(n) is derived numerically from the quantizer output y0(n) according to a particular adaptation algorithm. Except for the DC-level of s(n), sequence y0 (n) contains the full digital information of the modulator input signal. From y0(n), a digital multilevel sequence w0 (n) can be calculated, which represents the digital modulator output. The price paid for the improved SNR is a moderate slew rate limitation of the input signal. The approach is basically suited for a wide class of sigma-delta modulators. Here, simulation results and an example for a practical implementation of an adaptive sigma-delta modulator of first order are presented.