Neuropathological effects of chronically implanted, intracortical microelectrodes in a tetraplegic patient.

Objective.Intracortical microelectrode arrays (MEA) can be used as part of a brain-machine interface system to provide sensory feedback control of an artificial limb to assist persons with tetraplegia. Variability in functionality of electrodes has been reported but few studies in humans have examined the impact of chronic brain tissue responses revealed postmortem on electrode performancein vivo. Approach.In a tetraplegic man, recording MEAs were implanted into the anterior intraparietal area and Brodmann's area 5 (BA5) of the posterior parietal cortex and a recording and stimulation array was implanted in BA1 of the primary somatosensory cortex (S1). The participant expired from unrelated causes seven months after MEA implantation. The underlying tissue of two of the three devices was processed for histology and electrophysiological recordings were assessed.Main results.Recordings of neuronal activity were obtained from all three MEAs despite meningeal encapsulation. However, the S1 array had a greater encapsulation, yielded lower signal quality than the other arrays and failed to elicit somatosensory percepts with electrical stimulation. Histological examination of tissues underlying S1 and BA5 implant sites revealed localized leptomeningeal proliferation and fibrosis, lymphocytic infiltrates, astrogliosis, and foreign body reaction around the electrodes. The BA5 recording site showed focal cerebral microhemorrhages and leptomeningeal vascular ectasia. The S1 site showed focal tissue damage including vascular recanalization, neuronal loss, and extensive subcortical white matter necrosis. The tissue response at the S1 site included hemorrhagic-induced injury suggesting a likely mechanism for reduced function of the S1 implant.Significance.Our findings are similar to those from animal studies with chronic intracortical implants and suggest that vascular disruption and microhemorrhage during device implantation are important contributors to overall array and individual electrode performance and should be a topic for future device development to mitigate tissue responses. Neurosurgical considerations are also discussed.

Intraspinal stimulation with a silicon-based 3D chronic microelectrode array for bladder voiding in cats.

Objective.Bladder dysfunction is a significant and largely unaddressed problem for people living with spinal cord injury (SCI). Intermittent catheterization does not provide volitional control of micturition and has numerous side effects. Targeted electrical microstimulation of the spinal cord has been previously explored for restoring such volitional control in the animal model of experimental SCI. Here, we continue the development of the intraspinal microstimulation array technology to evaluate its ability to provide more focused and reliable bladder control in the feline animal model.Approach.For the first time, a mechanically robust intraspinal multisite silicon array was built using novel microfabrication processes to provide custom-designed tip geometry and 3D electrode distribution. Long-term implantation was performed in eight spinally intact animals for a period up to 6 months, targeting the dorsal gray commissure area in the S2 sacral cord that is known to be involved in the coordination between the bladder detrusor and the external urethral sphincter.Main results.About one third of the electrode sites in the that area produced micturition-related responses. The effectiveness of stimulation was further evaluated in one of eight animals after spinal cord transection (SCT). We observed increased bladder responsiveness to stimulation starting at 1 month post-transection, possibly due to supraspinal disinhibition of the spinal circuitry and/or hypertrophy and hyperexcitability of the spinal bladder afferents.Significance. 3D intraspinal microstimulation arrays can be chronically implanted and provide a beneficial effect on the bladder voiding in the intact spinal cord and after SCT. However, further studies are required to assess longer-term reliability and safety of the developed intraspinal microstimulation array prior to eventual human translation.

PRIMA subretinal wireless photovoltaic microchip implantation in non-human primate and feline models.

PURPOSE: To evaluate the surgical technique for subretinal implantation of two sizes of PRIMA photovoltaic wireless microchip in two animal models, and refine these surgical procedures for human trials. METHODS: Cats and Macaca fascicularis primates with healthy retina underwent vitrectomy surgery and were implanted with subretinal wireless photovoltaic microchip at the macula/central retina. The 1.5mm PRIMA chip was initially studied in feline eyes. PRIMA implant (2mm,1.5mm sizes) arrays were studied in primates. Feasibility of subretinal chip implantation was evaluated with a newly-developed surgical technique, with surgical complications and adverse events recorded. RESULTS: The 1.5mm implant was placed in the central retina of 11 feline eyes, with implantation duration 43-106 days. The 1.5mm implant was correctly positioned into central macula of 11 primate eyes, with follow-up periods of minimum 6 weeks (n = 11), 2 years (n = 2), and one eye for 3 years. One primate eye underwent multi-chip 1.5mm implantation using two 1.5mm chips. The 2mm implant was delivered to 4 primate eyes. Optical coherence tomography confirmed correct surgical placement of photovoltaic arrays in the subretinal space in all 26 eyes. Intraoperative complications in primate eyes included retinal tear, macular hole, retinal detachment, and vitreous hemorrhage that resolved spontaneously. Postoperatively, there was no case of significant ocular inflammation in the 1.5mm implant group. CONCLUSIONS: We report subretinal implantation of 1.5mm and 2mm photovoltaic arrays in the central retina of feline and central macula of primate eyes with a low rate of device-related complications. The in vivo PRIMA implantation technique has been developed and refined for use for a 2mm PRIMA implant in ongoing human trials.

Electrical performance of penetrating microelectrodes chronically implanted in cat cortex.

Penetrating microelectrode arrays with 2000 µm (2) sputtered iridium oxide (SIROF) electrode sites were implanted in cat cerebral cortex, and their long-term electrochemical performance evaluated in vivo by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and current pulsing. Measurements were made from days 33 to 328 postimplantation. The CV-defined charge storage capacity, measured at 50 mV/s, increased linearly with time over the course of implantation for two arrays and was unchanged for one array. A modest decrease in 1 kHz impedance was also observed. These results suggest an ongoing increase in the apparent electrochemical surface area of the electrodes, which is attributed to electrical leakage pathways arising from cracking of Parylene insulation observed by SEM of explanted arrays. During current pulsing with a 0.0 V interpulse bias, the electrodes readily delivered 8 nC/phase in vitro, but some channels approached or exceeded the water reduction potential during in vivo pulsing. The charge injection capacity in vivo increased linearly with the interpulse bias (0-0.6 V Ag\vert AgCl) from 11.5 to 21.8 nC/ph and with pulse width (150-500 µs) from 8.8 to 14 nC/ph (at 0.0 V bias). These values are lower than those determined from measurements in buffered physiological saline, emphasizing the importance of in vivo measurements in assessing chronic electrode performance. The consequence of current leakage pathways on the charge-injection measurements is also discussed.

In vivo validation of custom-designed silicon-based microelectrode arrays for long-term neural recording and stimulation.

We developed and validated silicon-based neural probes for neural stimulating and recording in long-term implantation in the brain. The probes combine the deep reactive ion etching process and mechanical shaping of their tip region, yielding a mechanically sturdy shank with a sharpened tip to reduce insertion force into the brain and spinal cord, particularly, with multiple shanks in the same array. The arrays' insertion forces have been quantified in vitro. Five consecutive chronically-implanted devices were fully functional from 3 to 18 months. The microelectrode sites were electroplated with iridium oxide, and the charge injection capacity measurements were performed both in vitro and after implantation in the adult feline brain. The functionality of the chronic array was validated by stimulating in the cochlear nucleus and recording the evoked neuronal activity in the central nucleus of the inferior colliculus. The arrays' recording quality has also been quantified in vivo with neuronal spike activity recorded up to 566 days after implantation. Histopathology evaluation of neurons and astrocytes using immunohistochemical stains indicated minimal alterations of tissue architecture after chronic implantation.

Electrical performance of penetrating microelectrodes chronically implanted in cat cortex.

Penetrating multielectrode arrays with electrode coatings of sputtered iridium oxide (SIROF) have been implanted chronically in cat cortex for periods over 300 days. The ability of these electrodes to inject charge at levels above expected thresholds for neural excitation has been examined in vivo by measurements of voltage transients in response to current-controlled, cathodal stimulation pulsing. The effect of current pulse width from 150 µs to 500 µs and voltage biasing of the electrodes in the interpulse period at two levels, 0.0 V and 0.6 V vs. Ag|AgCl, were also investigated. The results of in vivo characterization of the electrodes by open-circuit potential measurements, cyclic voltammetry and impedance spectroscopy are also reported.

Bidirectional telemetry controller for neuroprosthetic devices.

We present versatile multifunctional programmable controller with bidirectional data telemetry, implemented using existing commercial microchips and standard Bluetooth protocol, which adds convenience, reliability, and ease-of-use to neuroprosthetic devices. Controller, weighing 190 g, is placed on animal's back and provides bidirectional sustained telemetry rate of 500 kb/s , allowing real-time control of stimulation parameters and viewing of acquired data. In continuously-active state, controller consumes approximately 420 mW and operates without recharge for 8 h . It features independent 16-channel current-controlled stimulation, allowing current steering; customizable stimulus current waveforms; recording of stimulus voltage waveforms and evoked neuronal responses with stimulus artifact blanking circuitry. Flexibility, scalability, cost-efficiency, and a user-friendly computer interface of this device allow use in animal testing for variety of neuroprosthetic applications. Initial testing of the controller has been done in a feline model of brainstem auditory prosthesis. In this model, the electrical stimulation is applied to the array of microelectrodes implanted in the ventral cochlear nucleus, while the evoked neuronal activity was recorded with the electrode implanted in the contralateral inferior colliculus. Stimulus voltage waveforms to monitor the access impedance of the electrodes were acquired at the rate of 312 kilosamples/s. Evoked neuronal activity in the inferior colliculus was recorded after the blanking (transient silencing) of the recording amplifier during the stimulus pulse, allowing the detection of neuronal responses within 100 mus after the end of the stimulus pulse applied in the cochlear nucleus.

Spinal hyperexcitability and bladder hyperreflexia during reversible frontal cortical inactivation induced by low-frequency electrical stimulation in the cat.

Spinal hyperexcitability and hyperreflexia gradually develop in the majority of stroke patients. These pathologies develop as a result of reduced cortical modulation of spinal reflexes, mediated largely indirectly via relays in the brainstem and other subcortical structures. Cortical control of spinal reflexes is markedly different in small animals, such as rodents, while in some larger species, such as cats, it is more comparable to that in humans. In this study, we developed a novel model of stroke in the cat, with controllable and reversible inhibition of cortical neuronal activity appearing approximately 1h after initiation of low-frequency electrical stimulation in the frontal cerebral cortex, evidenced by a large increase in the alpha frequency band (7-14 Hz) of the frontal electrocorticographic signal. Hyperreflexia of the urinary bladder developed 3h or more after induction of reversible cortical inactivation with optimized stimulation parameters (frequency of 1-2 Hz, amplitude of 10 mA, applied for 30 min). The bladder hyperreflexia persisted for at least 8h, and disappeared within 24h. At the S2 level of the spinal cord, where neural circuits mediating micturition and other pelvic reflexes reside, we have recorded an increase in neuronal activity correlated with the development of hyperreflexia. The low-frequency stimulation-induced reversible cortical inactivation model of stroke is highly reproducible and allows evaluation of spinal hyperexcitability and hyperreflexia using within-animal comparisons across experimental conditions, which can be of great value in examination of mechanisms of spinal hyperreflexia following stroke or brain trauma, and for developing more effective treatments for these conditions.

Audiologic outcomes with the penetrating electrode auditory brainstem implant.

OBJECTIVE: The penetrating electrode auditory brainstem implant (PABI) is an extension of auditory brainstem implant (ABI) technology originally developed for individuals deafened by neurofibromatosis type 2. Whereas the conventional ABI uses surface electrodes on the cochlear nuclei, the PABI uses 8 or 10 penetrating microelectrodes in conjunction with a separate array of 10 or 12 surface electrodes. The goals of the PABI were to use microstimulation to reduce threshold current levels, increase the range of pitch percepts, and improve electrode selectivity and speech recognition. PATIENTS AND PROTOCOL: In a prospective clinical trial, 10 individuals, all with neurofibromatosis type 2, received a PABI after vestibular schwannoma removal via a translabyrinthine approach. All study participants met strict requirements for informed consent as part of a Food and Drug Administration clinical trial. Approximately 8 weeks after implantation, PABI devices were activated and tested at our tertiary clinical and research facility. Mean follow-up time was 33.8 months. STUDY DESIGN: Using a single-subject design, we measured thresholds and dynamic ranges, electrode-specific pitch percepts, and speech perception performance at regular intervals. RESULTS: Penetrating electrodes produced auditory thresholds at substantially lower charge levels than surface electrodes, a wide range of electrode-specific pitch sensations, and minimal cross-electrode interference and could be used in speech maps either alone or in combination with surface electrodes. However, less than 25% of penetrating electrodes resulted in auditory sensations, whereas more than 60% of surface electrodes were effective. Even after more than 3 years of experience, patients using penetrating electrodes did not achieve improved speech recognition compared with those using surface electrode ABIs. In patients with usable penetrating electrodes, City University of New York Sentence Test scores with sound and visual information were 61.6% in the PABI group and 64.7% in a surface ABI cohort (p = not significant). CONCLUSION: The PABI met the goals of lower threshold, increased pitch range, and high selectivity, but these properties did not result in improved speech recognition.

A new chronic neural probe with electroplated iridium oxide microelectrodes.

We have developed a silicon-based neural microelectrode system for long-term neural recording and stimulation. Our aim is to design robust silicon-based microelectrode arrays that are suitable for implantation into various targets in the brain and spinal cord. The microelectrode sites were electroplated with iridium oxide, thereby reducing the AC impedance and increasing charge storage capacity, compared to gold electrodes. To date, the implanted probe system has been able to record resolvable single-unit action potentials for five months in the ventral cochlear nucleus of the cats' brainstem.

Intraspinal stimulation for bladder voiding in cats before and after chronic spinal cord injury.

The long-term objective of this study is to develop neural prostheses for people with spinal cord injuries who are unable to voluntarily control their bladder. This feasibility study was performed in 22 adult cats. We implanted an array of microelectrodes into locations in the sacral spinal cord that are involved in the control of micturition reflexes. The effect of microelectrode stimulation was studied under light Propofol anesthesia at monthly intervals for up to 14 months. We found that electrical stimulation in the sacral parasympathetic nucleus at S(2) level or in adjacent ventrolateral white matter produced bladder contractions insufficient for inducing voiding, while stimulation at or immediately dorsal to the dorsal gray commissure at S(1) level produced strong (at least 20 mmHg) bladder contractions as well as strong (at least 40 mm Hg) external urethral sphincter relaxation, resulting in bladder voiding in 14 animals. In a subset of three animals, spinal cord transection was performed. For several months after the transection, intraspinal stimulation continued to be similarly or even more effective in inducing the bladder voiding as before the transection. We speculate that in the absence of the supraspinal connections, the plasticity in the local spinal circuitry played a role in the improved responsiveness to intraspinal stimulation.

Basis of electrical stimulation of the cochlea and the cochlear nucleus.

Sensorineural hearing loss is the most common form of deafness in humans. In patients with a severe-profound sensorineural hearing loss therapeutic intervention can only be achieved by direct electrical stimulation of the auditory nerve via a cochlear implant, or - in cases where a cochlear implant is not a surgical option - neurons within the central auditory pathway via an auditory brainstem implant. This paper reviews the basis of electrical stimulation of these structures with an emphasis on pathophysiology and safety.

Evaluation of the stability of intracortical microelectrode arrays.

In order to use recorded neural activities from the brain as control signals for neuroprosthesis devices, it is important to maintain a stable interface between chronically implanted microelectrodes and neural tissue. Our previous paper introduced a method to quantify the stability of the recording microelectrodes. In this paper, the method is refined 1) by incorporating stereotypical behavioral patterns into the spike sorting program and 2) by using a classifier based on Bayes theorem for assigning the recorded action potentials to the underlying neural generators. An improved method for calculating stability index is proposed. The results for the stability of microelectrode arrays that differ in structure are presented.

Over-pulsing degrades activated iridium oxide films used for intracortical neural stimulation.

Microelectrodes using activated iridium oxide (AIROF) charge-injection coatings have been pulsed in cat cortex at levels from near-threshold for neural excitation to the reported in vitro electrochemical charge-injection limits of AIROF. The microelectrodes were subjected to continuous biphasic current pulsing, using an 0.4V (versus Ag|AgCl) anodic bias with equal cathodal and anodal pulse widths, for periods up to 7h at a frequency of either 50Hz or 100Hz. At charge densities of 3mC/cm(2), histology revealed iridium-containing deposits in tissue adjacent to the charge-injection sites and scanning electron microscopy of explanted electrodes revealed a thickened and poorly adherent AIROF coating. Microelectrodes pulsed at 2mC/cm(2) or less remained intact, with no histologic evidence of non-biologic deposits in the tissue. AIROF microelectrodes challenged in vitro under the same pulsing conditions responded similarly, with electrodes pulsed at 3mC/cm(2) showing evidence of AIROF delamination after only 100s of pulsing at 100Hz (10,000 pulses total), while electrodes pulsed at 2mC/cm(2) for 7h at 50Hz (1.3 x 10(6) pulses total) showed no evidence of damage. In vitro electrochemical potential transient measurements in buffered physiologic saline indicate that polarizing the AIROF beyond the potential window for electrolysis of water (-0.6 to 0.8V versus Ag|AgCl) results in the observed degradation.

Neuroprotection of ischemic brain by vascular endothelial growth factor is critically dependent on proper dosage and may be compromised by angiogenesis.

Vascular endothelial growth factor (VEGF) is currently considered a potential pharmacologic agent for stroke therapy because of its strong neuroprotective and angiogenic capacities. Nonetheless, it is unclear how neuroprotection and angiogenesis by exogenous VEGF are related and whether they are concurrent events. In this study, the authors evaluated by stereology the effect of VEGF on neuronal and vascular volume densities of normal and ischemic brain cortices of adult male Sprague-Dawley rats. Ischemia was induced by a 4-hour occlusion of the middle cerebral artery. Low, intermediate, and high doses of VEGF165 were infused through the internal carotid artery for 7 days by an indwelling osmotic pump. The low and intermediate doses, which did not induce angiogenesis, significantly promoted neuroprotection of ischemic brains and did not damage neurons of normal brains. In contrast, the high dose that induced angiogenesis showed no neuroprotection of ischemic brains and damaged neurons of normal brains. These findings suggest that in vivo neuroprotection of ischemic brains by exogenous VEGF does not necessarily occur simultaneously with angiogenesis. Instead, neuroprotection may be greatly compromised by doses of VEGF capable of inducing angiogenesis. Stroke intervention efforts attempting to induce neuroprotection and angiogenesis concurrently through VEGF monotherapy should be approached with caution.

Mapping of spinal cord circuits controlling the bladder and external urethral sphincter functions in the rabbit.

AIMS: A primary purpose of this study was to evaluate the rabbit as a model for studying the spinal circuitry controlling the bladder emptying. We aimed to map the locations of the neuronal circuitry controlling the external urethral sphincter (EUS) and the detrusor by stimulating at different spinal cord locations with a microelectrode, while recording the responses from these muscles. METHODS: Spinal cord microstimulation was performed in the intermediate zone of the gray matter at the L7-S4 spinal cord levels in eight rabbits with empty and full bladders. Bladder activity was measured as intravesical pressure (IVP) changes and EUS activity was measured via electromyographic (EMG) electrodes positioned within the urethra. RESULTS: Under both bladder conditions, EUS activation was produced from similar locations in the spinal cord comprising a continuous area in the intermediate zone of the S2-S3 spinal cord. This region extended 25 mm in the rostrocaudal dimension, at least 1 mm lateral to the midline, and 0.5-1 mm in the dorsoventral dimension at a depth of 2-3 mm beneath the dorsal surface. No locations in the intermediate zone produced EUS inhibition. The S2-S3 spinal region, stimulation of which produced the strongest EUS activation, also produced modest bladder contractions. CONCLUSIONS: Overall, the results indicate that spinal cord networks controlling bladder and EUS activation in the rabbit are overlapping and clustered into columns extending rostrocaudally. The lack of spinal locations producing EUS inhibition and large bladder contractions make the rabbit an unattractive model for studies of neuroprosthetic spinal control of micturition.

The effects of prolonged intracortical microstimulation on the excitability of pyramidal tract neurons in the cat.

This study was conducted to examine the excitability changes induced in cerebral cortical neurons during prolonged microstimulation with a spatially dense microelectrodes array. The arrays of 16 iridium microelectrodes were implanted chronically into the postcruciate gyrus of cats. Neuronal responses characteristic of single pyramidal tract axons (ULRs) were recorded in the medullary pyramid. 7 h of pulsing of individual electrodes at 50 Hz and at 4 nC/ph induced little or no change in the ULRs' electrical thresholds. The thresholds also were quite stable when 4 of the 16 microelectrodes were pulsed on each of 14 consecutive days. However, when all 16 microelectrodes were pulsed for 7 h at 4 nC/ph, the threshold of approximately half of the ULRs became elevated. Recovery of excitability required 2-18 days. Prolonged sequential (interleaved) pulsing of the 16 microelectrodes induced less depression of excitability than did simultaneous pulsing, but only when the stimulus amplitude was low (12 A, 1.8 nC/ph). Stimulation at a higher amplitude (15 nC/ph) induced much more depression of excitability. These findings imply that multiple processes mediate the stimulation-induced depression of neuronal excitability. The data also demonstrate that the depression can be reduced by employing a stimulus regimen in which the inherent spatial resolution of the array is maximized (sequential pulsing at an amplitude in which there is minimal overlap of the effective current fields).