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Biomedical subjects

Joseph F Rizzo

Publications and source records attributed to Joseph F Rizzo.

At least 19 recordsLinked to original sources
PubMed2007

Neurotrophin-eluting hydrogel coatings for neural stimulating electrodes.

Improved sensory and motor prostheses for the central nervous system will require large numbers of electrodes with low electrical thresholds for neural excitation. With the eventual goal of reducing stimulation thresholds, we have investigated the use of biodegradable, neurotrophin-eluting hydrogels (i.e., poly(ethylene glycol)-poly(lactic acid), PEGPLA) as a means of attracting neurites to the surface of stimulating electrodes. PEGPLA hydrogels with release rates ranging from 1.5 to 3 weeks were synthesized. These hydrogels were applied to multielectrode arrays with sputtered iridium oxide charge-injection sites. The coatings had little impact on the iridium oxide electrochemical properties, including charge storage capacity, impedance, and voltage transients during current pulsing. Additionally, we quantitatively examined the ability of neurotrophin-eluting, PEGPLA hydrogels to promote neurite extension in vitro using a PC12 cell culture model. Hydrogels released neurotrophin (nerve growth factor, NGF) for at least 1 week, with neurite extension near that of an NGF positive control and much higher than extension seen from sham, bovine serum albumin-releasing boluses, and a negative control. These results show that neurotrophin-eluting hydrogels can be applied to multielectrode arrays, and suggest a method to improve neuron-electrode proximity, which could result in lowered electrical stimulation thresholds. Reduced thresholds support the creation of smaller electrode structures and high density electrode prostheses, greatly enhancing prosthesis control and function.

Animals↗
PubMed2006

In vivo electrical stimulation of rabbit retina: effect of stimulus duration and electrical field orientation.

Information that defines the depth of activation of retinal neurons is useful in considering strategies for stimulation with a retinal prosthesis, or interpreting the results from human studies that have previously been performed. The purpose of this study was to test the assertion that electrical pulse durations >0.5 msec preferentially stimulate retinal neurons deep to the ganglion cell layer. Thirteen Dutch-belted rabbits (1.2-2.0 kg) were used in this study. A Goldmann-like dome was used to deliver photic stimuli to the retina to measure the electroretinogram (ERG) and the light-induced cortical potential (VECP). Then, a micromanipulator was used to position a 500 microm inner diameter bipolar electrode near the visual streak on the epi-retinal surface. Symmetric biphasic pulses (7-1600 microA; 0.25 msec and 2.0 msec pulses per phase; biphasic pulses delivered at 2 Hz) were delivered to the retina with a current source. Extra-dural electrodes were used to record electrical evoked cortical potentials (EECPs) over the occipital cortex by performing 50 consecutive computer-averaged stimulations. The effect on the EECP of sequential epi-retinal (i.e. return electrode on epi-retinal surface) vs. trans-retinal (i.e. return electrode behind sclera) stimulation was compared. The effect upon the ERG, VECP and EECP was then assessed after 2,3,dihydroxy-6-nitro-7-sulfamoyl-benzo-f-quinoxaline (NBQX) at 112 microM concentration, d-2-amino-7-phosphonoheptanoic acid (D-AP7) at 1200 microM concentration, and l-amino-4-phosphonobutyrate (APB) at 300 microM concentration were delivered into the vitreous cavity to selectively block neuronal input to the retinal ganglion cells. Median values were reported. The amplitudes of the light-induced ERG and VECP were markedly reduced by instillation of the intra-vitreal synaptic blocking drugs. By comparison, pharmacological blockade of input to the retinal ganglion cells did not significantly alter the threshold charge or amplitude of the electrically-induced cortical responses (P>0.05). For the electrical stimuli, there was no significant difference in threshold charge for the EECP for epi-retinal vs. trans-retinal stimulation (P>0.05). The amplitude of the EECP increased linearly with increasing charge using both 0.25 msec and 2.0 msec pulses, even after synaptic blockade of input to the ganglion cells. The lack of obvious degradation of cortical amplitudes after drug instillation indicates that neurons of the middle retina are not being preferentially driven with epi-retinal stimulation, at least not with stimulus pulses up to 2.0 msec in duration. This conclusion is in contrast to prior evidence that 2.0 msec pulses would preferentially stimulate deeper retinal neurons, specifically the bipolar cells. Based upon our own observations in other studies, we believe that preferential stimulation of the middle retina in fact can be achieved by epi-retinal stimulation, by using pulse durations at least 5 times longer than those used in this study.

2-Amino-5-phosphonovalerate↗
PubMed2006

Thresholds for activation of rabbit retinal ganglion cells with a subretinal electrode.

The ultimate success of a retinal prosthesis to create vision will likely depend upon developing a base of knowledge of how best to electrically stimulate the retina. Previously, we studied the responses of rabbit retinal ganglion cells (RGCs) to current pulses applied with an electrode placed on the epiretinal surface. In the present study, we examined the responses of rabbit RGCs to current pulses applied with a subretinal electrode. Single-unit extracellular recordings were made from OFF RGCs and ON RGCs in isolated retinas, which were stimulated with monophasic current pulses (0.1-50ms in duration), delivered through a 500-mum diameter electrode. All RGCs elicited one or more bursts of action potentials upon electrical stimulation of the retina. The timing of the bursts depended upon both the polarity of the electrical stimulus and the RGC type. With near-threshold current pulses, the response latencies of OFF RGCs to anodal stimulation were comparable to those of ON RGCs to cathodal stimulation, whereas the response latencies of OFF RGCs to cathodal stimulation were comparable to those of ON RGCs to anodal stimulation. Threshold currents for activation of RGCs decreased with increased pulse duration. For OFF RGCs, threshold currents for cathodal current pulses were, on average, 2-7.5 times higher (depending upon pulse duration) than the threshold currents for anodal current pulses. For ON RGCs, threshold currents for cathodal and anodal current pulses were, on average, nearly identical for all pulse durations and were equivalent to threshold currents of OFF RGCs to anodal stimulation. With respect to a subretinal prosthesis, our findings suggest the possibility that cathodal current pulses may bias activation of ON RGCs in blind patients.

Action Potentials↗
PubMed2006

Ischemic optic neuropathy following spine surgery in a 16-year-old patient and a ten-year-old patient.

Peri-operative ischemic optic neuropathy typically occurs in middle-aged or older patients. We report this condition in two patients aged 16 and 10 years. Only six other cases of peri-operative ischemic optic neuropathy have been reported in patients aged less than 30 years, all but one occurring after spinal surgery. Although the visual prognosis appears to be more favorable in younger patients, the pathogenesis of this rare complication of surgery is likely to be the same as that affecting older individuals.

Adolescent↗
PubMed2006

Biocompatibility of materials implanted into the subretinal space of Yucatan pigs.

PURPOSE: To assess the biocompatibility of materials for possible use in subretinal prostheses. METHODS: Strips (0.5 x 5 mm; 10-microm thick) of either plain poly(imide) or poly(imide) coated with amorphous aluminum oxide (AAO), amorphous carbon (AC), parylene, poly(vinyl pyrrolidone) (PVP), or poly(ethylene glycol) (PEG) were each implanted into the subretinal space of four Yucatan miniature pigs. Two types of control surgery without implantation were performed in four other animals. Electroretinograms (ERGs) were performed before and after surgery. All animals were euthanatized 3 months after surgery, and histologic slides of the retina were assessed for 15 criteria. Paired, two-tailed Student's t-tests were used for statistical analyses. RESULTS: Across all animals, the mean amplitude of the ERG b-wave did not differ from baseline after 3 months. In implanted animals, the histologic analyses revealed that (1) all the implanted materials produced abnormalities that were significantly greater than in the control subjects; (2) overall, PEG, parylene, and PVP produced less histologic disruption than the other three materials; (3) parylene and PEG did not differ significantly from the control in disturbing retinal anatomy; (4) only PI and AAO produced RPE alterations that were significantly greater than in control subjects; and (5) AAO and PI produced a significantly greater degree of peri-implant cellular responses than did the other materials. CONCLUSIONS: All implants produced some alteration of the retina, but there were clear differences among the materials in the degree to which their presence disturbed the normal anatomy of the retina or RPE or incited tissue reactions around the implant.

Animals↗
PubMed2005

In vitro activation of retinal cells: estimating location of stimulated cell by using a mathematical model.

Activation of neurons at different depths within the retina and at various eccentricities from the stimulating electrode will presumably influence the visual percepts created by a retinal prosthesis. With an electrical prosthesis, neurons will be activated in relation to the stimulating charge that impacts their cell membranes. The common model used to predict charge density is Coulomb's law, also known as the square law. We propose a modified model that can be used to predict neuronal depth that takes into account: (1) finite dimensions related to the position and size of the stimulating and return electrodes and (2) two-dimensional displacements of neurons with respect to the electrodes, two factors that are not considered in the square law model. We tested our model by using in vitro physiological threshold data that we had obtained previously for eight OFF-center brisk-transient rabbit retinal ganglion cells. For our most spatially dense threshold data (25 microm increments up to 100 microm from the cell body), our model estimated the depth of one RGC to be 76 +/- 76 microm versus 87 +/- 62 microm (median: SD) for the square law model, respectively. This difference was not statistically significant. For the seven other RGCs for which we had obtained threshold data up to 800 microm from the cell body, the estimate of the RGC depth (using data obtained along the X axis) was 96 +/- 74 versus 20 +/- 20 microm for the square law and our modified model, respectively. Although this difference was not statistically significant (Student t-test: p = 0.12), our model provided median values much closer to the estimated depth of these RGCs (>>25 microm). This more realistic estimate of cell depth predicted by our model is not unexpected in this latter data set because of the more spatially distributed threshold data points that were evaluated. Our model has theoretical advantages over the traditional square law model under certain conditions, especially when considering neurons that are horizontally displaced from the stimulating electrode. Our model would have to be tested with a larger threshold data pool to permit more conclusive statements about the relative value of our model versus the traditional square law model under special circumstances.

Action Potentials↗
PubMed2005

Responses of rabbit retinal ganglion cells to electrical stimulation with an epiretinal electrode.

Rational selection of electrical stimulus parameters for an electronic retinal prosthesis requires knowledge of the electrophysiological responses of retinal neurons to electrical stimuli. In this study, we examined the effects of cathodal and anodal current pulses on the extracellularly recorded responses of OFF and ON rabbit retinal ganglion cells (RGCs) in an in vitro preparation. Current pulses (1 msec duration), delivered by a 125 microm electrode placed on the inner retinal surface within the receptive field of a RGC, produced both short-latency (< or =5 msec) and long-latency (8-60 msec) responses. The long-latency responses, but not the short-latency responses, were abolished upon application of the glutamate receptor antagonists CNQX and NBQX, thus indicating that the long-latency responses of RGCs are due to activation of presynaptic neurons in the retina. The latency of the long-latency response depended upon the polarity of the stimulus. For OFF RGCs, the average latency was 11 msec for a cathodal stimulus and 24 msec for an anodal stimulus. For ON RGCs, the average latency was 25 msec for a cathodal stimulus and 16 msec for an anodal stimulus. The threshold current also depended upon the polarity of the stimulus, at least for OFF RGCs. The average threshold current for evoking a long-latency response in OFF RGCs was 10 microA for a cathodal stimulus and 21 microA for an anodal stimulus. In ON RGCs, the average threshold current was 13 microA for a cathodal stimulus and 15 microA for an anodal stimulus.

Action Potentials↗
PubMed2005

Comparison of electrically evoked cortical potential thresholds generated with subretinal or suprachoroidal placement of a microelectrode array in the rabbit.

The aim of the study was to directly compare the threshold electrical charge density of the retina (retinal threshold) in rabbits for the generation of electrical evoked potentials (EEP) by delivering electrical stimulation with a custom-made microelectrode array (MEA) implanted into either the subretinal or suprachoroidal space. Nine eyes of seven Dutch-belted rabbits were studied. The electroretinogram (ERG), visual evoked potentials (VEP) and EEP were recorded. Electrodes for the VEP and EEP were placed on the dura mater overlying the visual cortex. The EEP was recorded following electrical stimulation of the MEA placed either subretinally beneath the visual streak of the retina or in the suprachoroidal space in the rabbit eye. An ab externo approach was used for placement of the MEA. Liquid perfluorodecaline (PFCL; 0.4 ml) was placed within the vitreous cavity to flatten the neurosensory retina on the MEA after subretinal implantation. The retinal threshold for generation of an EEP was determined for each MEA placement by three consecutive measurements consisting of 100 computer-averaged recordings. Animals were sacrificed at the conclusion of the experiment and the eyes were enucleated for histological examination. The retinal threshold to generate an EEP was 9 +/- 7 nC (0.023 +/- 0.016 mC cm(-2)) within the subretinal space and 150 +/- 122 nC (0.375 +/- 0.306 mC cm(-2)) within the suprachoroidal space. Histology showed disruption of the outer retina with subretinal but not suprachoroidal placement. The retinal threshold to elicit an EEP is significantly lower with subretinal placement of the MEA compared to suprachoroidal placement (P < 0.05). The retinal threshold charge density with a subretinal MEA is well below the published charge limit of 1 mC cm(-2), which is the level below which chronic stimulation of the retina is considered necessary to avoid tissue damage (Shannon 1992 IEEE Trans. Biomed. Eng. 39 424-6).

Animals↗
PubMed2005

Delayed visual decline in patients with "stable" optic neuropathy.

BACKGROUND: Histological studies on the human optic nerve have documented decreasing axonal nerve fiber counts with age. In patients with optic atrophy, a nonpathological dropout of ganglion cell axons as part of the normal aging process may become clinically significant. OBJECTIVE: To describe the occurrence of delayed visual loss in patients with presumably "stable" optic neuropathy. METHODS: We reviewed the medical records of 3 patients who experienced slowly progressive visual loss in adulthood after suffering childhood optic nerve injury. RESULTS: All 3 patients had a monophasic illness in childhood that caused bilateral optic atrophy and visual impairment. Following decades of stability, each suffered a gradual, symptomatic visual decline that extended over years. No new ophthalmologic, systemic, or neurologic disorder was found that explained the visual decline in any of these patients. CONCLUSION: We hypothesize that the late visual decline in these 3 patients resulted from deleterious effects of age-related axonal loss on an already depleted population of neurons.

Age of Onset↗
PubMed2005

What blindness can tell us about seeing again: merging neuroplasticity and neuroprostheses.

Significant progress has been made in the development of visual neuroprostheses to restore vision in blind individuals. Appropriate delivery of electrical stimulation to intact visual structures can evoke patterned sensations of light in those who have been blind for many years. However, success in developing functional visual prostheses requires an understanding of how to communicate effectively with the visually deprived brain in order to merge what is perceived visually with what is generated electrically.

Animals↗
PubMed2005

Thresholds for activation of rabbit retinal ganglion cells with relatively large, extracellular microelectrodes.

PURPOSE: To investigate the responses of retinal ganglion cells (RGCs) to electrical stimulation, using electrodes comparable in size to those used in human studies investigating the feasibility of an electronic retinal prosthesis. METHODS: Rabbit retinas were stimulated in vitro with current pulses applied to the inner surface with 125- and 500-mum diameter electrodes while the responses of RGCs were recorded extracellularly. RESULTS: Both short-latency (SL; 3-5 ms) and long-latency (LL; >/=9 ms) responses were observed after electrical stimulation within the receptive field of an RGC. With short, 0.1-ms current pulses, the threshold current for the SL cell response was significantly lower than that for the LL cell response. With long (10- to 20-ms) pulses, the threshold currents for the SL and LL cell responses were very similar. The threshold current for the SL cell response increased more steeply than did the LL cell response when the electrode was displaced from the point of lowest electrical threshold, either above or along the surface of the retina. Stimulation of an RGC axon outside of the cell's receptive field produced only an SL response. For 0.1-ms duration pulses, the threshold current for the axonal response was significantly higher than the threshold current for the SL cell response. At pulse durations > 1 ms, the thresholds were very similar. CONCLUSIONS: RGC responses to electrical stimulation depend on the current pulse duration and location of the stimulating electrode. For an epiretinal prosthesis, short-duration current pulses may be preferable since they result in a more localized activation of the retina.

Animals↗
PubMed2004

Outer retinal degeneration: an electronic retinal prosthesis as a treatment strategy.

OBJECTIVE: To review progress toward an electronic retinal prosthesis for outer retinal degeneration. METHOD: Literature review. RESULTS: Retinal degenerations such as retinitis pigmentosa result in a loss of photoreceptors. There is a secondary loss of inner retinal cells, but significant numbers of bipolar and ganglion cells remain for many years. Electrical stimulation can produce phosphenes in the eyes of individuals who are blind as a result of retinitis pigmentosa. Several research groups are trying to exploit this phenomenon to produce artificial vision with electronic retinal prostheses. Two groups, with private company sponsorship, have recently implanted first-generation devices in subjects with advanced retinitis pigmentosa. They have reported limited preliminary results. This article seeks to put these results in a broader context and review potential obstacles to successful prosthesis development. These include inner retinal cell viability, high thresholds, signal encoding, power requirements, biocompatibility, and device encapsulation. CONCLUSION: There has been substantial progress toward an electronic retinal prosthesis, but fully functional, long-lasting devices are not on the immediate horizon.

Biocompatible Materials↗
PubMed2004

Optic nerve head circulation in nonarteritic anterior ischemic optic neuropathy and optic neuritis.

PURPOSE: To quantify optic nerve head circulatory abnormalities in patients with unilateral nonarteritic anterior ischemic optic neuropathy (NAION) or optic neuritis (ON), and to assess the potential of such measurements to differentiate NAION from ON. DESIGN: Prospective, cross-sectional, observational study. PARTICIPANTS: Thirty consecutive patients with unilateral NAION, 22 consecutive patients with unilateral ON, and 50 healthy control subjects. METHODS: All subjects underwent a complete neuro-ophthalmologic evaluation. The widths of Doppler-broadened frequency spectra, which are directly proportional to the speed of blood cells flowing through the capillaries of the optic nerve head, were measured at multiple sites in both eyes of each subject. The variation of Doppler broadening (DB) with age was determined in the control subjects. Doppler broadening values in the patients were compared between similar sites in affected and contralateral eyes, and between both affected and contralateral eyes and the age-adjusted values determined in the control subjects. MAIN OUTCOME MEASURES: The differences in DB between (1) the affected and contralateral eyes of the patients, (2) the patients and the control subjects, and (3) the patients with NAION and those with ON. RESULTS: In NAION, DB was decreased at both temporal (-20.2% and -18.5%) and nasal (-12.8% and -12.4%) sites of the nerve head in affected eyes compared with contralateral eyes or eyes of control subjects. In ON, DB was also decreased at temporal sites (-11.3% and -9.2%) in affected eyes compared with contralateral or control eyes. At nasal sites, there were no significant differences in DB in affected eyes of ON patients compared with contralateral or control eyes. The DB decreases were significantly greater in NAION patients than in ON patients. CONCLUSIONS: Optic nerve head circulatory abnormalities are present in patients with NAION or ON. This is the first demonstration of such abnormalities in ON, a finding consistent with the recent attention given to the phenomenon of axonal loss in this disease. Although there are differences in the circulatory abnormalities between the 2 diseases that provide insights into the pathophysiological mechanisms at play, they are not large enough to enable the clinician to distinguish between ON and NAION in an individual patient.

Adolescent↗
PubMed2004

Identification of KIF21A mutations as a rare cause of congenital fibrosis of the extraocular muscles type 3 (CFEOM3).

PURPOSE: Three congenital fibrosis of the extraocular muscles phenotypes (CFEOM1-3) have been identified. Each represents a specific form of paralytic strabismus characterized by congenital restrictive ophthalmoplegia, often with accompanying ptosis. It has been demonstrated that CFEOM1 results from mutations in KIF21A and CFEOM2 from mutations in PHOX2A. This study was conducted to determine the incidence of KIF21A and PHOX2A mutations among individuals with the third CFEOM phenotype, CFEOM3. METHODS: All pedigrees and sporadic individuals with CFEOM3 in the authors' database were identified, whether the pedigrees were linked or consistent with linkage to the FEOM1, FEOM2, and/or FEOM3 loci was determined, and the appropriate pedigrees and the sporadic individuals were screened for mutations in KIF21A and PHOX2A. RESULTS: Twelve CFEOM3 pedigrees and 10 CFEOM3 sporadic individuals were identified in the database. The structures of eight of the pedigrees permitted the generation of meaningful linkage data. KIF21A was screened in 17 probands, and mutations were identified in two CFEOM3 pedigrees. One pedigree harbored a novel mutation (2841G-->A, M947I) and one harbored the most common and recurrent of the CFEOM1 mutations identified previously (2860C-->T, R954W). None of CFEOM3 pedigrees or sporadic individuals harbored mutations in PHOX2A. CONCLUSIONS: The results demonstrate that KIF21A mutations are a rare cause of CFEOM3 and that KIF21A mutations can be nonpenetrant. Although KIF21A is the first gene to be associated with CFEOM3, the results imply that mutations in the unidentified FEOM3 gene are the more common cause of this phenotype.

DNA Mutational Analysis↗
PubMed2004

Differential recovery of the electroretinogram, visually evoked cortical potential, and electrically evoked cortical potential following vitrectomy: implications for acute testing of an implanted retinal prosthesis.

To determine the extent to which electrophysiologic tests of the afferent visual pathway are affected by vitrectomy, the procedure was performed in 15 eyes of 11 adult Dutch-belted rabbits. An electroretinogram (ERG), visually evoked cortical potential (VECP), and electrically evoked cortical potential (EECP) were obtained preoperatively and sequentially after surgery. For electrical stimulations, biphasic impulses were delivered to the retina. Post-vitrectomy declines of 49, 25, and 41% from the median baseline amplitudes and increases of 13, 18, and 17% from the median baseline latency values were found for ERG, VECP, and EECP, respectively. At 90 min, 13 to 30% of eyes still had an amplitude more than 10% below baseline on at least one of the three tests, whereas 10 to 47% of eyes had an abnormal latency more than 10% above baseline on at least one of the three tests. Amplitudes were more likely than latencies to return to near baseline, but for eyes that remained subnormal, the decline was greater for amplitudes than latencies. Significant alterations in retinal function, manifested by declines in amplitudes and increases in latencies of the ERG, VECP, and EECP, persist in a large proportion of eyes up to 90 min post-vitrectomy.

Animals↗
PubMed2004

In vivo electrical stimulation of rabbit retina with a microfabricated array: strategies to maximize responses for prospective assessment of stimulus efficacy and biocompatibility.

PURPOSE: Our primary goal was to assess the effects of varying stimulus parameters on the electrically evoked cortical potentials (EECPs) in rabbits, which we intend to use as one measure of biocompatibility of implanted retinal prosthetic devices. We also sought to exclude contamination of waveforms recorded over the occipital cortex from electrical activity from the retina and the degree of reproducibility of EECP recordings. METHODS: A concentric bipolar platinum electrode or microfabricated 5x5 electrode array delivered current to the retina of 43 Dutch-belted rabbits while the EECP was recorded from extradural electrodes over the occipital cortex. Electroretinogram (ERG) and visual evoked cortical potential (VECP) recordings were routinely obtained. Verification that occipital cortical recordings were not heavily contaminated by electrical potentials from the retina (i.e. the "validity" of the cortical recordings) was made by recording retinal and brain responses before and after intravitreal injection of tetrodotoxin. Electrical stimulation of the retina was performed with monopolar (with distant return) or bipolar electrode configurations. Cortical responses were computer-averaged over 100-500 stimulations. The effect of variation in stimulus current, charge, duration, frequency, polarity and spatial orientation of stimulating electrodes on cortical responses was studied. RESULTS: Progressive reduction of responses toward the anterior skull and abolition of posterior recordings by tetrodotoxin indicated that retinal activity did not significantly contaminate EECP recordings. Reproducibility testing revealed that inter-animal variability within the first hour of testing across all animals was not significantly greater than that found during prolonged testing of a single animal. The lowest current that yielded a reproducible EECP with monopolar stimulation was 75 microA (total current through 21 electrodes) using 200 microsec pulses, which yielded a 45 microV cortical response. Strength-duration curves were generally flat for fixed charge stimulation and linear for fixed current stimulation, at least up to a saturation point, which occurred at very high charge. Over 0.5-16 Hz stimulus frequencies, ERGs varied little but evoked potential responses showed a monotonic decline in amplitude at higher frequencies. Large negative-going initial pulses of a biphasic pair yielded the largest cortical amplitudes. EECP amplitudes varied significantly with the orientation of stimulating electrodes on the retina. CONCLUSIONS: This study provides novel data on the reproducibility of EECP recordings, and insight into stimulation parameters that affect retinal and cortical responses. This information can be used to improve the yield of retinal and evoked potential recordings, which will enhance the prospective assessment of the efficacy of stimulation and health of the stimulated tissues following.

Anesthetics, Local↗