Carla J. Abbott

Relationship of the optical coherence tomography signal to underlying retinal histology in the tree shrew (Tupaia belangeri).

PURPOSE To interpret the retinal origin of the optical coherence tomography (OCT) signal by objectively (i.e., minimal investigator bias) aligning in vivo OCT longitudinal reflectivity profiles (LRPs) with corresponding vertical histologic sections. METHODS The Zeiss StratusOCT system was used to obtain retinal B-scans in vivo in eyes from adult tree shrews. Subsequently, the retinas were fixed and embedded. Semithin vertical sections through the retina were obtained from the same locations as the LRPs. A statistical correlation procedure that accounted for axial tissue shrinkage determined the best relationship between features in the LRP and sublaminae boundaries in corresponding histology sections. RESULTS For the optimal relationship, the three regions of high reflectivity in the inner OCT signal corresponded to (1) the nerve fiber and ganglion cell layers, (2) the inner plexiform layer and amacrine cell somas, and (3) the outer plexiform layer. The two regions of low reflectivity in the inner OCT signal corresponded to (1) the somas of Müller, bipolar, and horizontal cells in the inner nuclear layer and (2) the outer nuclear layer. The outer OCT signal had a region of high reflectivity that corresponded to the photoreceptor inner and outer segments, the pigment epithelium, Bruchs membrane, and at least part of the choriocapillaris. CONCLUSIONS These results provide a clear interpretation for the OCT signal in terms of the underlying retinal anatomy. This interpretation can be used in vivo to identify sublaminae affected by retinal disease and has implications for the origin of the inner OCT signal in human retina.

Retinal thinning in tree shrews with induced high myopia: Optical coherence tomography and histological assessment

This study determined retinal thinning in a mammalian model of high myopia using optical coherence tomography (OCT) and histological sections from the same retinal tissue. High myopia was induced in three tree shrews (Tupaia belangeri) by deprivation of form vision via lid suture of one eye, with the other eye a control. Ocular biometry data was obtained by Ascan ultrasonography, keratometry and retinoscopy. The Zeiss StratusOCT was used to obtain Bscans in vivo across the retina. Subsequently, eyes were enucleated and retinas fixed, dehydrated, embedded and sectioned. Treated eyes developed a high degree of axial myopia (-15.9 ± 2.3D; n = 3). The OCT analysis showed that in myopic eyes the nasal retina thinned more than the temporal retina relative to the disc (p=0.005). Histology showed that the retinas in the myopic eyes comprise all layers but were thinner than the retinas in normal and control eyes. Detailed thickness measurements in corresponding locations of myopic and control eyes in superior nasal retina using longitudinal reflectivity profiles from OCT and semithin vertical histological sections showed the percentage of retinal thinning in the myopic eyes was similar between methods (OCT 15.34 ± 5.69%; histology 17.61 ± 3.02%; p = 0.10). Analysis of retinal layers revealed that the inner plexiform, inner nuclear and outer plexiform layers thin the most. Cell density measurements showed all neuronal cell types are involved in retinal thinning. The results indicate that in vivo OCT measurements can accurately detect retinal thinning in high myopia.

Amacrine and bipolar inputs to midget and parasol ganglion cells in marmoset retina.

Retinal ganglion cells receive excitatory synapses from bipolar cells and inhibitory synapses from amacrine cells. Previous studies in primate suggest that the strength of inhibitory amacrine input is greater to cells in peripheral retina than to foveal (central) cells. A comprehensive study of a large number of ganglion cells at different eccentricities, however, is still lacking. Here, we compared the amacrine and bipolar input to midget and parasol ganglion cells in central and peripheral retina of marmosets (Callithrix jacchus). Ganglion cells were labeled by retrograde filling from the lateral geniculate nucleus or by intracellular injection. Presumed amacrine input was identified with antibodies against gephyrin; presumed bipolar input was identified with antibodies against the GluR4 subunit of the AMPA receptor. In vertical sections, about 40% of gephyrin immunoreactive (IR) puncta were colocalized with GABAA receptor subunits, whereas immunoreactivity for gephyrin and GluR4 was found at distinct sets of puncta. The density of gephyrin IR puncta associated with ganglion cell dendrites was comparable for midget and parasol cells at all eccentricities studied (up to 2 mm or about 16 degrees of visual angle for midget cells and up to 10 mm or >80 degrees of visual angle for parasol cells). In central retina, the densities of gephyrin IR and GluR4 IR puncta associated with the dendrites of midget and parasol cells are comparable, but the average density of GluR4 IR puncta decreased slightly in peripheral parasol cells. These anatomical results indicate that the ratio of amacrine to bipolar input does not account for the distinct functional properties of parasol and midget cells or for functional differences between cells of the same type in central and peripheral retina.

Development of a Magnetic Attachment Method for Bionic Eye Applications

Successful visual prostheses require stable, long-term attachment. Epiretinal prostheses, in particular, require attachment methods to fix the prosthesis onto the retina. The most common method is fixation with a retinal tack; however, tacks cause retinal trauma, and surgical proficiency is important to ensure optimal placement of the prosthesis near the macula. Accordingly, alternate attachment methods are required. In this study, we detail a novel method of magnetic attachment for an epiretinal prosthesis using two prostheses components positioned on opposing sides of the retina. The magnetic attachment technique was piloted in a feline animal model (chronic, nonrecovery implantation). We also detail a new method to reliably control the magnet coupling force using heat. It was found that the force exerted upon the tissue that separates the two components could be minimized as the measured force is proportionately smaller at the working distance. We thus detail, for the first time, a surgical method using customized magnets to position and affix an epiretinal prosthesis on the retina. The position of the epiretinal prosthesis is reliable, and its location on the retina is accurately controlled by the placement of a secondary magnet in the suprachoroidal location. The electrode position above the retina is less than 50 microns at the center of the device, although there were pressure points seen at the two edges due to curvature misalignment. The degree of retinal compression found in this study was unacceptably high; nevertheless, the normal structure of the retina remained intact under the electrodes.

Cannula-based drug delivery to the guinea pig round window causes a lasting hearing loss that may be temporarily mitigated by BDNF

ABSTRACT Sustained local delivery of drugs to the inner ear may be required for future regenerative and protective strategies. The round window is surgically accessible and a promising delivery route. To be viable, a delivery system should not cause hearing loss. This study determined the effect on hearing of placing a drug‐delivery microcatheter on to the round window, and delivering either artificial perilymph (AP) or brain‐derived neurotrophic factor (BDNF) via this catheter with a mini‐osmotic pump. Auditory brainstem responses (ABRs) were monitored for 4 months after surgery, while the AP or BDNF was administered for the first month. The presence of the microcatheter ‐ whether dry or when delivering AP or BDNF for 4 weeks ‐ was associated with an increase in ABR thresholds of up to 15 dB, 16 weeks after implantation. This threshold shift was, in part, delayed by the delivery of BDNF. We conclude that the chronic presence of a microcatheter in the round window niche causes hearing loss, and that this is exacerbated by delivery of AP, and ameliorated temporarily by delivery of BDNF.

Safety Studies for a 44-Channel Suprachoroidal Retinal Prosthesis: A Chronic Passive Study

Purpose Following successful clinical outcomes of the prototype suprachoroidal retinal prosthesis, Bionic Vision Australia has developed an upgraded 44-channel suprachoroidal retinal prosthesis to provide a wider field of view and more phosphenes. The aim was to evaluate the preclinical passive safety characteristics of the upgraded electrode array. Methods Ten normal-sighted felines were unilaterally implanted with an array containing platinum electrodes (44 stimulating and 2 returns) on a silicone carrier near the area centralis. Clinical assessments (color fundus photos, optical coherence tomography, full-field electroretinography, intraocular pressure) were performed under anesthesia prior to surgery, and longitudinally for up to 20 weeks. Histopathology grading of fibrosis and inflammation was performed in two animals at 13 to 15 weeks. Results Eight animals showed safe electrode array insertion (good retinal health) and good conformability of the array to the retinal curvature. Eight animals demonstrated good mechanical stability of the array with only minor (<2 disc diameters) lateral movement. Four cases of surgical or stability complications occurred due to (1) bulged choroid during surgery, (2) hemorrhage from a systemic bleeding disorder, (3) infection, and (4) partial erosion of thin posterior sclera. There was no change in retinal structure or function (other than that seen at surgery) at endpoint. Histopathology showed a mild foreign body response. Electrodes were intact on electrode array removal. Conclusions The 44-channel suprachoroidal electrode array has an acceptable passive safety profile to proceed to clinical trial. The safety profile is expected to improve in human studies, as the complications seen are specific to limitations (anatomic differences) with the feline model.

Neural responses to multielectrode stimulation of healthy and degenerate retina

Purpose Simultaneous stimulation of multiple retinal electrodes in normally sighted animals shows promise in improving the resolution of retinal prostheses. However, the effects of simultaneous stimulation on degenerate retinae remain unknown. Therefore, we investigated the characteristics of cortical responses to multielectrode stimulation of the degenerate retina. Methods Four adult cats were bilaterally implanted with retinal electrode arrays in the suprachoroidal space after unilateral adenosine triphosphate (ATP)-induced retinal photoreceptor degeneration. Functional and structural changes were characterized by using electroretinogram a-wave amplitude and optical coherence tomography. Multiunit activity was recorded from both hemispheres of the visual cortex. Responses to single- and multielectrode stimulation of the ATP-injected and fellow control eyes were characterized and compared. Results The retinae of ATP-injected eyes displayed structural and functional changes consistent with mid- to late-stage photoreceptor degeneration and remodeling. Responses to multielectrode stimulation of the ATP-injected eyes exhibited shortened latencies, lower saturated spike counts, and higher thresholds, compared to stimulation of the fellow control eyes. Electrical receptive field sizes were significantly larger in the ATP-injected eye than in the control eye, and positively correlated with the extent of degeneration. Conclusions Significant differences exist between cortical responses to stimulation of healthy and degenerate retinae. Our results highlight the importance of using a retinal degeneration model when evaluating the efficacy of novel stimulation paradigms.