The neuroprotective effect of hypothermia for mitigation of ischemic and hypoxic damage to the retina is well documented, yet technology to achieve targeted, controlled ocular hypothermia in vivo is lacking. This study evaluated controlled cooling of ocular tissues using a novel scleral contact eye cooler designed to be practical in a clinical setting. Excised fresh adult porcine eyes (n = 5) were imaged (at 9.4 T MRI) to document gross anatomy, instrumented with temperature sensors at five key locations, and partially lowered into a warm oil bath (37 °C) to represent surrounding extraocular tissues. A scleral contact ring (SCR) interfaced with an active heat pump was lowered to contact the eye. The SCR was brought to 4 °C and maintained at that temperature using feedback control while monitoring sensor temperatures. After the eye tissues reached thermal equilibrium in the cooled state, the experiment was terminated, and a micro-CT image was obtained to verify the location of each temperature sensor. Average equilibrium temperatures of the anterior sclera and optic nerve sensors were 10.7 and 30.2 °C, achieved within 3.2 and 11.7 min, respectively. These temperatures have been shown to be neuroprotective against hypoxic damage. In the non-perfused eye model, therapeutically relevant temperatures could be induced throughout the eye and maintained indefinitely. Demonstration of targeted and controlled cooling of eye tissues using a minimally invasive scleral contact ring will enable in vivo therapeutic hypothermia research using a design amenable to clinical translation.

Changes in the full-field flash and flicker electroretinogram (ERG) that accompany normal aging were evaluated in mice. ERGs were recorded from a single cohort of C57BL/6J mice from 5 to 70 weeks of age using conventional techniques. Dark-adapted ERGs were recorded for flash luminances of - 3.0 to 1.5 log cd-s-m-2; a- and b-wave amplitude and implicit time (IT) were calculated from these responses. In addition, light-adapted flicker ERGs elicited by sinusoidally modulated light were measured for temporal frequencies of 2 to 31 Hz. Amplitudes and phases were extracted from the flicker responses using Fourier analysis. Linear quantile mixed models were used for statistical comparisons of the effects of age on amplitude and timing. There was a significant decrease in a-wave amplitude (p < 0.001) and b-wave amplitude (p < 0.001) over the 65 week study. From 5 to 70 weeks, the a- and b-wave amplitudes decreased by a factor of approximately 2. There was a small (2-14 ms), but significant (p < 0.001), delay in a- and b-wave IT over the 65 week study. There was also a significant decrease in fundamental amplitude (factor of 1.8, p < 0.001) and second harmonic amplitude (factor of 1.5, p < 0.001) over time. There were no significant age-related effects on the phase of these components (both p > 0.06). These results indicate that age scales the single flash and flicker ERG similarly, reducing response amplitude by a factor of approximately 2, from 5 to 70 weeks, with small or no effect on response timing. These data may be useful for guiding future longitudinal pre-clinical therapeutic studies.

Localized hypothermia treatment can reduce the risk of vision loss due to ocular trauma. Hypothermia reduces inflammation and metabolic rate, and improves blood flow to prevent nerve and tissue damage. This paper presents a finite element thermal analysis to determine the efficacy of local hypothermia treatment administered using a scleral eye contact ring that acts as a heat sink. A realistic model of the human eye orbit, including fat and muscle, is created using MRI scans. A simplified CAD-based model is also created based on the first model. A transient analysis is performed by lowering the contact surface between the device and the eye to 4∘C. The study shows that the device lowers the temperature of the optic nerve head to a therapeutic range of 32-34∘C in less than 10 min of treatment, hence supporting the efficacy of such a device.

Objective. The spatial distribution of activity at the retina determines the spatial distribution of electroretinogram potentials at the cornea. Here a three-dimensional surface spline method is evaluated for interpolating corneal potentials between measurement points in multi-electrode electroretinography (meERG) data sets.Approach. 25-channel meERG responses were obtained from rat eyes before and after treatment to create local lesions. A 3rd order surface spline was used to interpolate meERG values resulting in smooth color-coded maps of corneal potentials. Potential maps were normalized using standard score values. Pre- and post-treatment responses were characterized by spatial standard deviation and by difference-from-normal plots.Main results. The spatial standard deviation for eyes with local lesions were significantly higher than for healthy eyes. The 3rd order spline resulted in well-behaved corneal potential maps that maintained low error rate when up to 30% of recording channels were excluded from analysis. Post-normalization, responses could be combined within experimental groups, and individual eyes with lesions were clearly distinguished from the healthy-eye mean response. A 3rd order surface spline is an acceptable means of interpolating meERG potentials to create corneal potential maps. The spatial standard deviation is more sensitive to local dysfunction than absolute amplitudes.Significance. This work demonstrates solutions to key challenges in the recording and analysis of meERG responses: visualization, normalization, channel loss, and identification of abnormal responses. Continued development of the meERG technique is relevant to research and clinical applications, especially where local dysfunction (early progressive disease) or local therapeutic effect (subretinal injection) is of interest.

The electroretinogram (ERG) is a functional test widely used in clinical practice to help diagnose diseases of the retina and optic nerve. In fact, it measures the electrical response to a light stimulus of retinal cells, and different ERG tests can be used to probe different retinal areas and cells. The stimulators most commonly used in visual electrophysiology are Ganzfeld stimulators, spherical devices used to perform full-field ERG, and flat monitors, which are not suited for the detection of peripheral early disfunctions, since they do not probe the entire human visual field. Clinical stimulators can use different technologies, but light emitting diodes (LEDs) are becoming very popular since they are almost ideal light sources. Recently, a three dimensional stimulus source based on LEDs able to perform peripheral pattern ERG (ppERG) has been developed. In this paper, a highly-configurable full-field stimulus source for electroretinography based on LEDs is presented. It is capable of presenting an arbitrary pattern of pixels to the entire visual field of a test subject, thus bringing together the functionalities of the existing stimulators. The pattern of pixels is configurable to present stimuli for multiple ERG protocols to any arbitrary sector of the visual field, giving also the possibility to use different colours. The device structure was designed in order to obtain uniform luminance stimuli and minimal light reflection. Moreover, programming and control of the device was widely explored, with a special focus on the development of an electronic design flexible enough to allow the implementation of different ERG protocols. Luminance uniformity of the device was analysed, obtaining satisfactory results. Considering the colour channel of greatest interest for pattern ERG (pERG) protocol, the contrast between black and white checks was much higher than the minimum 80% required by the standards. Finally, the prototyped device was able to elicit consistent flicker ERG and full-field ERG responses in a healthy volunteer subject.

Introduction. Academic and commercial research teams are currently developing a new generation of devices that will interact with, incorporate, and/or emulate living nervous systems. Neural prostheses to restore hearing, mobility or sight will offer a wider range of function; robotic devices will become more effective with “neuromorphic” control systems; fundamentally new methods for processing information will be motivated by biological systems. Neural Engineering is the intellectual force behind these developments, supported by recent advances in cellular neurobiology, microfabrication and neural modeling. Based on decades of quantitative approaches to increase our understanding of neural systems, bioengineers are now beginning to design neural systems and neural interfaces. Neural engineers have new tools to control aspects of these systems such as guided axon growth and multielectrode arrays for stimulation and recording. In addition to potential applications attracting the attention of biotech and defense industries, these efforts in turn increase our understanding of natural neural systems.

Objective: The information derived from the electroretinogram (ERG), especially with regard to local areas of retinal dysfunction or therapeutic rescue, can be enhanced by an increased understanding of the relationship between local retinal current sources and local ERG potentials measured at the cornea. A critical step in this direction is the development of a robust bioelectric field model of the ERG. Methods: A finite-element model was created to simulate ERG potentials at the cornea resulting from physiologically relevant transretinal currents. A magnetic resonance image of a rat eye was segmented to define all major ocular structures, tissues were assigned conductivity values from the literature. The model was optimized to multi-electrode ERG (meERG) data recorded in healthy rat eyes, and validated with meERG data from eyes with experimental lesions in peripheral retina. Results: Following optimization, the simulated distribution of corneal potentials was in good agreement with measured values; residual error was comparable to the average difference of individual eyes from the measured mean. The model predicted the corneal potential distribution for eight eyes with experimental lesions with similar accuracy, and a measure of pre- to post-lesion changes in corneal potential distribution was well correlated with the location of the lesion. Conclusion: An eye model with high anatomical accuracy was successfully validated against a robust dataset. Significance: This model can now be used for optimization of ERG electrode design, and to support functional mapping of the retina from me ERG data via solving the inverse bioelectric source problem.

PURPOSE:The pattern electroretinogram (pERG) response reflects, in part, ganglion cell function. However, probing retinal ganglion cell (RGC) function in the mid- and far peripheral retina is difficult with conventional flat-panel pERG stimulus sources. A pattern stimulus source is presented for probing the peripheral retina. Peripheral pERG (ppERG) responses were evaluated versus luminance, reversal rate, and field subtended, and were compared with conventional pERG in healthy eyes. METHODS:Eleven normally-sighted subjects were recruited. A hemispherical surface was used to present a reversing checkerboard pattern to the peripheral retina, from approximately 35° to 85° of visual field, in all directions. Responses to stimuli presented to peripheral field sectors (superior, nasal, inferior, temporal) were also recorded. Conventional pERG responses were recorded on the same day. Amplitudes and implicit times of waveform peaks were evaluated. RESULTS:Robust pERG responses from peripheral retina resemble conventional pERG responses but with shorter implicit times and reduced positive component. Responses to high-luminance patterns include high-frequency components resembling flash ERG oscillatory potentials. Negative response component amplitudes increased with increasing pattern luminance, and decreased with increasing reversal rate. CONCLUSIONS:Peripheral-field pERG responses are robust and repeatable; the unique response properties reflect differences between central and peripheral retina. Field-sector response ratios can be used to probe for sectoral dysfunction associated with disease. TRANSLATIONAL RELEVANCE:The ppERG approach provides direct measurement of proximal retinal function beyond the fields probed by conventional perimetry and pERG, providing access to a relatively under studied part of the retina relevant to early stage glaucoma.