Implantable Neural Prostheses Research Articles

A Biomimetic, SoC-Based Neural Stimulator for Novel Arbitrary-Waveform Stimulation Protocols.

Novel neural stimulation protocols mimicking biological signals and patterns have demonstrated significant advantages as compared to traditional protocols based on uniform periodic square pulses. At the same time, the treatments for neural disorders which employ such protocols require the stimulator to be integrated into miniaturized wearable devices or implantable neural prostheses. Unfortunately, most miniaturized stimulator designs show none or very limited ability to deliver biomimetic protocols due to the architecture of their control logic, which generates the waveform. Most such designs are integrated into a single System-on-Chip (SoC) for the size reduction and the option to implement them as neural implants. But their on-chip stimulation controllers are fixed and limited in memory and computing power, preventing them from accommodating the amplitude and timing variances, and the waveform data parameters necessary to output biomimetic stimulation. To that end, a new stimulator architecture is proposed, which distributes the control logic over three component tiers – software, microcontroller firmware and digital circuits of the SoC, which is compatible with existing and future biomimetic protocols and with integration into implantable neural prosthetics. A portable prototype with the proposed architecture is designed and demonstrated in a bench-top test with various known biomimetic output waveforms. The prototype is also tested in vivo to deliver a complex, continuous biomimetic stimulation to a rat model of a spinal-cord injury. By delivering this unique biomimetic stimulation, the device is shown to successfully reestablish the connectivity of the spinal cord post-injury and thus restore motor outputs in the rat model.

A Feasibility Study on Optically Transparent Encapsulation for Implantable Neural Prostheses.

Optically transparent encapsulation is presented with results from long-term reliability and light transmission tests. This technology is required in certain implantable neural prostheses that demand the transmission of optical signals through an encapsulating material, such as in retinal implants or in optogenetic applications. In this study, biocompatible film-type cyclic olefin polymers (COPs) with low moisture absorption (<; 0.01 %) and high light transmission (92 %) are utilized as encapsulating materials based on thermal lamination. The reliability of COP encapsulation is characterized through accelerated soak tests in a 75 °C saline solution to measure the leakage currents from encapsulated inter-digitated electrodes. These tests had been done for 211 days with the estimated lifetime of 8.05 years at 37 °C. In addition, the optical properties of a thermally laminated COP film sample in relation to its thickness are evaluated by an experimental setup which uses projected line patterns on an image sensor. The light transmittance of COP film samples thinner than 376 μm exceeded 91.69 %, and the minimum distinguishable line pitch was 47.6 μm at a thickness of 26 μm. These results validate the feasibility of optically transparent encapsulation using COPs and may contribute to its use in future implantable neural prostheses.

Durable soft neural micro-electrode coating by an electrochemical synthesis of PEDOT:PSS / graphene oxide composites

The biocompatible neural interface has been one of the most difficult challenges in developing implantable active neural prostheses for more than a decade. Either in recording neural signals, which delivers intelligent signals to operate active prostheses or in stimulating living tissues, which aids sensing organ deficits, neural electrodes play central roles in relaying information between biotic tissues and abiotic electronics. Until now no single material can possess all the ideal physicochemical properties of chronically implantable neural electrodes although organic conducting polymers have demonstrated the most promising functional integration with neural tissues. Here, we have successfully constructed poly(3,4-ethylene dioxythiophene):poly(styrene sulfonate) (PEDOT:PSS)/graphene oxides (GOs) hybrid composites by electrochemical deposition on a gold micro-electrode. By changing the compositions and the redox states of GOs, the composites showed varied electrochemical performances as implantable neural electrodes, which have been further analyzed by Raman spectroscopy and scanning electron microscopy (SEM), and PC12 neural cellular attachment tests. Our experimental results indicated that both PEDOT:PSS/GOs and PEDOT:PSS/reduced graphene oxides (rGOs) were significantly better than PEDOT:PSS in electrochemical performances, mechanical softness, as well as favorable protein expressions of modulating PC12 neural cells. Therefore, our PEDOT:PSS/rGO composites can be used to further improve the PEDOT in the applications of an implantable electrode, biosensors, drug delivery carriers, and neural interfaces.

Totally Implantable Bidirectional Neural Prostheses: A Flexible Platform for Innovation in Neuromodulation.

Implantable neural prostheses are in widespread use for treating a variety of brain disorders. Until recently, most implantable brain devices have been unidirectional, either delivering neurostimulation without brain sensing, or sensing brain activity to drive external effectors without a stimulation component. Further, many neural interfaces that incorporate a sensing function have relied on hardwired connections, such that subjects are tethered to external computers and cannot move freely. A new generation of neural prostheses has become available, that are both bidirectional (stimulate as well as record brain activity) and totally implantable (no externalized connections). These devices provide an opportunity for discovering the circuit basis for neuropsychiatric disorders, and to prototype personalized neuromodulation therapies that selectively interrupt neural activity underlying specific signs and symptoms.

In Vivo Rat Spinal Cord and Striated Muscle Monitoring Using the Current Interruption Method and Bioimpedance Measurements

The therapeutic value of implantable neuroprosthetic devices would improve considerably if it were possible to monitor the electrical properties of the neural tissue, so that the stimuli to the nervous system can be optimally, efficiently and safely applied. The current interruption method (CIM) was previously described by the authors to obtain ex vivo electrical equivalent circuits (EECs) of rat liver and triceps surae (TS) tissues using a four-electrode arrangement, fractional calculus, and circuit theory. The aim of this paper was to investigate the use of CIM for in vivo real-time monitoring of rat spinal cord and striated muscle, as a prior step to addressing their potential uses in spinal cord injury or other conditions involving central nervous system (CNS) damage. Statistical analysis of the EEC parameter values was carried out to elucidate their physiological meaning and their possible uses in implantable neural prostheses.

An Implantable Wireless Neural Interface System for Simultaneous Recording and Stimulation of Peripheral Nerve with a Single Cuff Electrode.

Recently, implantable devices have become widely used in neural prostheses because they eliminate endemic drawbacks of conventional percutaneous neural interface systems. However, there are still several issues to be considered: low-efficiency wireless power transmission; wireless data communication over restricted operating distance with high power consumption; and limited functionality, working either as a neural signal recorder or as a stimulator. To overcome these issues, we suggest a novel implantable wireless neural interface system for simultaneous neural signal recording and stimulation using a single cuff electrode. By using widely available commercial off-the-shelf (COTS) components, an easily reconfigurable implantable wireless neural interface system was implemented into one compact module. The implantable device includes a wireless power consortium (WPC)-compliant power transmission circuit, a medical implant communication service (MICS)-band-based radio link and a cuff-electrode path controller for simultaneous neural signal recording and stimulation. During in vivo experiments with rabbit models, the implantable device successfully recorded and stimulated the tibial and peroneal nerves while communicating with the external device. The proposed system can be modified for various implantable medical devices, especially such as closed-loop control based implantable neural prostheses requiring neural signal recording and stimulation at the same time.

Miniature Elastomeric Valve Design for Safe Direct Current Stimulator.

For safety reasons, commercial neural implants use charge-balanced biphasic pulses to interact with target neurons using metal electrodes. Short biphasic pulses are used to avoid irreversible electrochemical reactions at the electrode-tissue interfaces. Biphasic pulses are effective at exciting neurons, but quite limited in inhibiting their activity. In contrast, direct current can both excite and inhibit neurons, however delivered to metal electrodes, it causes toxic electrochemical reactions. We recently introduced Safe Direct Current Stimulator (SDCS) technology, which can excite or inhibit neurons without violating the safety criteria. Instead of direct current, SDCS generates an ionic direct current (iDC) from a biphasic input signal using a network of fluidic channels and mechanical valves. A key enabler towards transforming SDCS concept from a benchtop design to an implantable neural prosthesis is the design of a miniature valve. In this work, we present poly-dimethylsiloxane (PDMS) based elastomeric valves, squeeze valve (SV) and plunger valve (PV) capable of being actuated using a shape memory alloy wire.

Implantable neurotechnologies: a review of integrated circuit neural amplifiers.

Neural signal recording is critical in modern day neuroscience research and emerging neural prosthesis programs. Neural recording requires the use of precise, low-noise amplifier systems to acquire and condition the weak neural signals that are transduced through electrode interfaces. Neural amplifiers and amplifier-based systems are available commercially or can be designed in-house and fabricated using integrated circuit (IC) technologies, resulting in very large-scale integration or application-specific integrated circuit solutions. IC-based neural amplifiers are now used to acquire untethered/portable neural recordings, as they meet the requirements of a miniaturized form factor, light weight and low power consumption. Furthermore, such miniaturized and low-power IC neural amplifiers are now being used in emerging implantable neural prosthesis technologies. This review focuses on neural amplifier-based devices and is presented in two interrelated parts. First, neural signal recording is reviewed, and practical challenges are highlighted. Current amplifier designs with increased functionality and performance and without penalties in chip size and power are featured. Second, applications of IC-based neural amplifiers in basic science experiments (e.g., cortical studies using animal models), neural prostheses (e.g., brain/nerve machine interfaces) and treatment of neuronal diseases (e.g., DBS for treatment of epilepsy) are highlighted. The review concludes with future outlooks of this technology and important challenges with regard to neural signal amplification.

Mechanical reliability of ceramic packages for active implantable medical devices - The IEC hammer test

Implantable neural prostheses have to fulfill manifold requirements, from the technological side as well as legally. One particular normative demand for active implantable medical devices (AIMDs) which are intended to be implanted in the skull, is withstanding a mechanical impact of 2.5 J, defined by BS EN 45502-2-3:2010 and IEC 60068-2-75:1997. This article shows two computational approaches based on finite element modeling to evaluate the influence of geometrical variations on a brain-computer interfaces' mechanical package stability and the likelihood of withstanding mechanical impact. The presence of a fillet at inner edges (&amp;gt;0.5 mm) as well as a minimum wall thickness of 1 mm could be identified as a mandatory design requirements for axially symmetric packages to avoid extensively high stress levels. Mechanical event simulation (MES) predicted a passing of the hammer test if additional protective material (silicone rubber) is used. This however is postulated by the EN 45502-2-3 standard. The computational findings could be confirmed in a laboratory setup of the impact test.

Temperature elevation profile inside the rat brain induced by a laser beam

The thermal effect may be a desired outcome or a concerning side effect in laser-tissue interactions. Research in this area is particularly motivated by recent advances in laser applications in diagnosis and treatment of neurological disorders. Temperature as a side effect also limits the maximum power of optical transfer and harvesting of energy in implantable neural prostheses. The main objective was to investigate the thermal effect of a near-infrared laser beam directly aimed at the brain cortex. A small, custom-made thermal probe was inserted into the rat brain to make direct measurements of temperature elevations induced by a free-air circular laser beam. The time dependence and the spatial distribution of the temperature increases were studied and the maximum allowable optical power was determined to be 2.27 W/cm2 for a corresponding temperature increase of 0.5°C near the cortical surface. The results can be extrapolated for other temperature elevations, where the margin to reach potentially damaging temperatures is more relaxed, by taking advantage of linearity. It is concluded that the thermal effect depends on several factors such as the thermal properties of the neural tissue and of its surrounding structures, the optical properties of the particular neural tissue, and the laser beam size and shape. Because so many parameters play a role, the thermal effect should be investigated for each specific application separately using realistic in vivo models.

A hardware-algorithm co-design approach to optimize seizure detection algorithms for implantable applications

Implantable neural prostheses that deliver focal electrical stimulation upon demand are rapidly emerging as an alternate therapy for roughly a third of the epileptic patient population that is medically refractory. Seizure detection algorithms enable feedback mechanisms to provide focally and temporally specific intervention. Real-time feasibility and computational complexity often limit most reported detection algorithms to implementations using computers for bedside monitoring or external devices communicating with the implanted electrodes. A comparison of algorithms based on detection efficacy does not present a complete picture of the feasibility of the algorithm with limited computational power, as is the case with most battery-powered applications. We present a two-dimensional design optimization approach that takes into account both detection efficacy and hardware cost in evaluating algorithms for their feasibility in an implantable application. Detection features are first compared for their ability to detect electrographic seizures from micro-electrode data recorded from kainate-treated rats. Circuit models are then used to estimate the dynamic and leakage power consumption of the compared features. A score is assigned based on detection efficacy and the hardware cost for each of the features, then plotted on a two-dimensional design space. An optimal combination of compared features is used to construct an algorithm that provides maximal detection efficacy per unit hardware cost. The methods presented in this paper would facilitate the development of a common platform to benchmark seizure detection algorithms for comparison and feasibility analysis in the next generation of implantable neuroprosthetic devices to treat epilepsy.

Properties of the Stimulus Router System, a Novel Neural Prosthesis

Various types of neural prostheses (NPs) have been developed to restore motor function after neural injury. Surface NPs are noninvasive and inexpensive, but are often poorly selective, activating nontargeted muscles and cutaneous sensory nerves that can cause discomfort or pain. Implantable NPs are highly selective, but invasive and costly. The stimulus router system (SRS) is a novel NP consisting of fully implanted leads that "capture" and route some of the current flowing between a pair of surface electrodes to the vicinity of a target nerve. An SRS lead consists of a "pick-up" terminal that is implanted subcutaneously under one of the surface electrodes and a "delivery" terminal that is secured on or near the target nerve. We have published a preliminary report on the basic properties of the SRS [L. S. Gan , "A new means of transcutaneous coupling for neural prostheses," IEEE Trans. Biomed. Eng., vol. 54, no. 3, pp. 509-517, Mar. 2007]. Here, we further characterize the SRS and identify aspects that maximize its performance as a motor NP. The surface current needed to activate nerves with an SRS, was found to depend on the proximity of the delivery terminal(s) to the nerve, electrode configurations, contact areas of the surface electrodes and implanted terminals, and the distance between the surface anode and the delivery terminal.

Responses of fibroblasts and glial cells to nanostructured platinum surfaces

The chronic performance of implantable neural prostheses is affected by the growth ofencapsulation tissue onto the stimulation electrodes. Encapsulation is associated withactivation of connective tissue cells at the electrode’s metallic contacts, usually made ofplatinum. Since surface nanotopography can modulate the cellular responses to materials,the aim of the present work was to evaluate the ‘in vitro’ responses of connective tissuecells to platinum strictly by modulating its surface nanoroughness. Using molecular beamepitaxy combined with sputtering, we produced platinum nanostructured substratesconsisting of irregularly distributed nanopyramids and investigated their effect on theproliferation, cytoskeletal organization and cellular morphology of primary fibroblasts andtransformed glial cells. Cells were cultured on these substrates and their responses tosurface roughness were studied. After one day in culture, the fibroblasts were moreelongated and their cytoskeleton less mature when cultured on rough substrates. This effectincreased as the roughness of the surface increased and was associated with reduced cellproliferation throughout the observation period (4 days). Morphological changesalso occurred in glial cells, but they were triggered by a different roughness scaleand did not affect cellular proliferation. In conclusion, surface nanotopographymodulates the responses of fibroblasts and glial cells to platinum, which may be animportant factor in optimizing the tissue response to implanted neural electrodes.

Sacral Neuromodulation in Women With Idiopathic Detrusor Overactivity Incontinence: Decreased Overactivity but Unchanged Bladder Contraction Strength and Urethral Resistance During Voiding

We evaluated the effect of sacral (S3) nerve neuromodulation on voiding in women with idiopathic detrusor overactivity incontinence. Urodynamic measurements in all patients implanted in 1990 to 2003 were reconsidered. Patients were included if these measurements, which were done at baseline and after 6 months, could be analyzed completely and reliably. Maximum detrusor pressure, amplitude of the highest involuntary detrusor contraction and end fill volume were used as parameters characterizing the degree of detrusor overactivity. Urethral resistance and bladder contraction strength during voiding were characterized by the bladder outlet obstruction index, the urethral resistance factor, average pressure, the slope of the low pressure side of the pressure flow plot, the bladder contractility index and the bladder contraction strength parameter. A total of 33 women were included. Detrusor overactivity parameters were significantly improved at followup. In addition, the supine position of the patient during filling in followup measurements proved less provocative with respect to overactivity than the standing position in the majority of measurements at baseline. Consequently bladder volumes at which voiding was initiated were considerably higher at followup. Changes in the parameters characterizing urethral resistance and bladder contraction strength during voiding were not unambiguous. However, exactly those parameters that appeared volume independent in a previous study were not significantly different. Our study confirmed the depressant effect of sacral (S3) nerve neuromodulation on detrusor overactivity. No effect on urethral resistance and bladder contraction strength during voiding could be demonstrated using volume independent parameters.

Iridium Oxide as a Stimulating Neural Electrode Formed by Reactive Magnetron Sputtering

Implantable neural prostheses form hybrid interfaces with biological constructs, and the application of electrical fields can restore functions of patients with neurological damages. The various stoichiometric compositions of iridium oxide were synthesized using reactive magnetron sputtering. The charge injection behavior of iridium oxide deposited with an O2/Ar ratio of 0.5 was similar to pure Ir. The charge density of iridium oxide increased with increasing O2/Ar ratio, and increasing thickness of iridium oxide.

Neuroprostheses to treat neurogenic bladder dysfunction: current status and future perspectives.

Neural prostheses are a technology that uses electrical activation of the nervous system to restore function to individuals with neurological or sensory impairment. This article provides an introduction to neural prostheses and lists the most successful neural prostheses (in terms of implanted devices). The article then focuses on neurogenic bladder dysfunction and describes two clinically available implantable neural prostheses for treatment of neurogenic bladder dysfunction. Special attention is given to the usage of these neural prostheses in children. Finally, three new developments that may lead to a new generation of implantable neural prostheses for bladder control are described. They may improve the neural prostheses currently available and expand further the population of patients who can benefit from a neural prosthesis.

Neural prostheses.

Assuming that neural regeneration after spinal cord injury (SCI) will eventually become a clinical reality, functional recovery will probably remain incomplete. Assistive devices will therefore continue to play an important role in rehabilitation. Neural prostheses (NPs) are assistive devices that restore functions lost as a result of neural damage. NPs electrically stimulate nerves and are either external or implanted devices. Surface stimulators for muscle exercise are now commonplace in rehabilitation clinics and many homes. Regarding implantable NPs, since 1963 over 40 000 have been implanted to restore hearing, bladder control and respiration. Epidural spinal cord stimulators and deep brain stimulators are routinely implanted to control pain, spasticity, tremor and rigidity. Implantable NPs have also been developed to restore limb movements using electrodes tunnelled under the skin to muscles and nerves. Spinal cord microstimulation (SC[mu]stim) is under study as an alternative way of restoring movement and bladder control. Improvement in bladder and bowel function is a high priority for many SCI people. Sacral root stimulation to elicit bladder contraction is the current NP approach, but this usually requires dorsal rhizotomies to reduce reflex contractions of the external urethral sphincter. It is possible that the spinal centres coordinating the bladder-sphincter synergy could be activated with SC[mu]stim. Given the large and growing number of NPs in use or development, it is surprising how little is known about their long-term interactions with the nervous system. Physiological research will play an important role in elucidating the mechanisms underlying these interactions.

INFLUENCE OF SACRAL NEUROMODULATION ON ELECTROSENSATION OF THE LOWER URINARY TRACT

We prospectively investigated whether neuromodulation of the S3 root influences the sensory threshold to electrical stimulation in the lower urinary tract. The study included 7 women and 3 men receiving S3 neuromodulation at 210 msec. and 25 Hz. with the Interstim PNE system for a mean of 5 days. Neuromodulation was done unilaterally in 6 cases and bilaterally in 4. The sensory threshold was determined by electrodes placed randomly against the mucosa of the empty bladder on the left and right sides, in the urethra in women, and in the prostatic and penile urethra in men. Thresholds were measured at each location with neuromodulation on and off. With bilateral neuromodulation on all 4 patients had a lower bladder threshold than with neuromodulation off. In unilateral neuromodulation the threshold was significantly lower during neurostimulation on the ipsilateral side. There was no effect on the threshold on the arm or in the urethra. The effect was noted in patients in whom neuromodulation was and was not clinically successful. Neuromodulation on S3 influences the nervous system involved in electrosensation of the bladder but not the skin afferent innervation or the nerves involved in urethral electrosensation. These data support the hypothesis that S3 neurostimulation is effective mainly through the afferent nervous system in the pelvic nerves.

Micromachined, Polyimide-Based Devices for Flexible Neural Interfaces

Micromachining technologies were established to fabricate microelectrode arrays and devices for interfacing parts of the central or peripheral nervous system in case of neuronal disorders. The devices were part of a neural prosthesis that allows simultaneous multichannel recording and multisite stimulation of neurons. Overcoming the brittle mechanics of silicon, we established a process technology to fabricate light-weighted and highly flexible polyimide based devices. Concerning the challenging housing demands close to the nerve to prevent mechanical induced nerve traumatization, we integrated interconnects to decouple the nerve interface from plugs and signal processing electronics. Hybrid integration with a new assembling technique—the MicroFlex interconnection (MFI)—has been applied for the connection of the flexible microsystems to silicon microelectronics. In this paper, we present different shapes and applications of the flexible electrodes: sieve electrodes for regeneration studies, cuff electrodes for interfacing peripheral nerves, and a retina implant for ganglion cell stimulation. The discussion is focused on electrode and material properties and the hybrid assembly of a fully implantable neural prosthesis.

Discussion: Assessment of symptoms in patients with an overactive bladder

I n patients with overactive bladder symptoms, urinary incontinence (UI) may be a manifestation of involuntary bladder contractions. Some patients with overactive bladder symptoms can be diagnosed solely by clinical evaluation, although others require objective diagnostic measures, such as pad tests and cystometry. Urodynamic assessment, including cystometry, remains the cornerstone when a precise diagnosis of the etiology underlying UI is required. Many incontinent patients with overactive bladder are treated with medical or behavioral therapy initially, with surgical treatment, such as bladder augmentation and chronic electrical sacral nerve stimulation using an implantable neural prosthesis is considered if initial treatments fail. Each of the therapeutic interventions is costly, and most are recognized as having bothersome side effects. Therefore, if treatment efficacy for a patient with overactive bladder symptoms is evaluated only by clinical judgment and objective diagnostic measures, the result is inaccurate. The complete evaluation of patients with overactive bladder symptoms requires the inclusion of quality-of-life (QOL) measures. We have used five grades of the subjective degree of bother for five symptoms (daytime frequency, nocturia, urgency, urge incontinence, and sensation of incomplete emptying) to evaluate the effect of anticholinergic drugs on the overactive bladder. The five grades of subjective degree of bother are as