Faculty Bibliography

Since the introduction of commercial optical coherence tomography (OCT) systems, the ophthalmic imaging modality has rapidly expanded and it has since changed the paradigm of visualization of the retina and revolutionized the management and diagnosis of neuro-retinal diseases, including glaucoma. OCT remains a dynamic and evolving imaging modality, growing from time-domain OCT to the improved spectral-domain OCT, adapting novel image analysis and processing methods, and onto the newer swept-source OCT and the implementation of adaptive optics (AO) into OCT. The incorporation of AO into ophthalmic imaging modalities has enhanced OCT by improving image resolution and quality, particularly in the posterior segment of the eye. Although OCT previously captured in-vivo cross-sectional images with unparalleled high resolution in the axial direction, monochromatic aberrations of the eye limit transverse or lateral resolution to about 15-20 mum and reduce overall image quality. In pairing AO technology with OCT, it is now possible to obtain diffraction-limited resolution images of the optic nerve head and retina in three-dimensions, increasing resolution down to a theoretical 3 mum3. It is now possible to visualize discrete structures within the posterior eye, such as photoreceptors, retinal nerve fiber layer bundles, the lamina cribrosa, and other structures relevant to glaucoma. Despite its limitations and barriers to widespread commercialization, the expanding role of AO in OCT is propelling this technology into clinical trials and onto becoming an invaluable modality in the clinician's arsenal.

Although it is well documented that abnormal levels of either intraocular (IOP) or intracranial pressure (ICP) can lead to potentially blinding conditions, such as glaucoma and papilledema, little is known about how the pressures actually affect the eye. Even less is known about potential interplay between their effects, namely how the level of one pressure might alter the effects of the other. Our goal was to measure in-vivo the pressure-induced stretch and compression of the lamina cribrosa due to acute changes of IOP and ICP. The lamina cribrosa is a structure within the optic nerve head, in the back of the eye. It is important because it is in the lamina cribrosa that the pressure-induced deformations are believed to initiate damage to neural tissues leading to blindness. An eye of a rhesus macaque monkey was imaged in-vivo with optical coherence tomography while IOP and ICP were controlled through cannulas in the anterior chamber and lateral ventricle, respectively. The image volumes were analyzed with a newly developed digital image correlation technique. The effects of both pressures were highly localized, nonlinear and non-monotonic, with strong interactions. Pressure variations from the baseline normal levels caused substantial stretch and compression of the neural tissues in the posterior pole, sometimes exceeding 20%. Chronic exposure to such high levels of biomechanical insult would likely lead to neural tissue damage and loss of vision. Our results demonstrate the power of digital image correlation technique based on non-invasive imaging technologies to help understand how pressures induce biomechanical insults and lead to vision problems.

OBJECTIVE: Several attributes of female reproductive history, including age at natural menopause (ANM), have been related to primary open-angle glaucoma (POAG). We assembled 18 previously reported common genetic variants that predict ANM to determine their association with ANM or POAG. METHODS: Using data from the Nurses' Health Study (7,143 women), we validated the ANM weighted genetic risk score in relation to self-reported ANM. Subsequently, to assess the relation with POAG, we used data from 2,160 female POAG cases and 29,110 controls in the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (NEIGHBORHOOD), which consists of 8 datasets with imputed genotypes to 5.6+ million markers. Associations with POAG were assessed in each dataset, and site-specific results were meta-analyzed using the inverse weighted variance method. RESULTS: The genetic risk score was associated with self-reported ANM (P = 2.2 x 10) and predicted 4.8% of the variance in ANM. The ANM genetic risk score was not associated with POAG (Odds Ratio (OR) = 1.002; 95% Confidence Interval (CI): 0.998, 1.007; P = 0.28). No single genetic variant in the panel achieved nominal association with POAG (P >/=0.20). Compared to the middle 80 percent, there was also no association with the lowest 10 percentile or highest 90 percentile of genetic risk score with POAG (OR = 0.75; 95% CI: 0.47, 1.21; P = 0.23 and OR = 1.10; 95% CI: 0.72, 1.69; P = 0.65, respectively). CONCLUSIONS: A genetic risk score predicting 4.8% of ANM variation was not related to POAG; thus, genetic determinants of ANM are unlikely to explain the previously reported association between the two phenotypes.This is an open-access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share thework provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0.

The mechanism that maintains a stable blood flow in the brain despite changes in cerebral perfusion pressure (CPP), and therefore guaranties a constant supply of oxygen and nutrients to the neurons, is known as cerebral autoregulation (CA). In a certain range of CPP, blood flow is mediated by a vasomotor adjustment in vascular resistance through dilation of blood vessels. CA is known to be impaired in diseases like traumatic brain injury, Parkinson's disease, stroke, hydrocephalus and others. If CA is impaired, blood flow and pressure changes are coupled and the oxygen supply might be unstable. Lassen's blood flow autoregulation curve describes this mechanism, where a plateau of stable blood flow in a specific range of CPP corresponds to intact autoregulation. Knowing the limits of this plateau and maintaining CPP within these limits can improve patient outcome. Since CPP is influenced by both intracranial pressure and arterial blood pressure, long term changes in either can lead to autoregulation impairment. Non-invasive methods for monitoring blood flow autoregulation are therefore needed. We propose to use Near infrared spectroscopy (NIRS) to fill this need. NIRS is an optical technique, which measures microvascular changes in cerebral hemoglobin concentration. We pe erformed experiments on non-human primates during exsanguination to demonstrate that the limits of blood flow autoregulation can be accessed with NIRS.

PURPOSE: To assess the effect of the previously reported optical coherence tomography (OCT) signal normalization method on reducing the discrepancies in image appearance among spectral-domain OCT (SD-OCT) devices. METHODS: Healthy eyes and eyes with various retinal pathologies were scanned at the macular region using similar volumetric scan patterns with at least two out of three SD-OCT devices at the same visit (Cirrus HD-OCT, Zeiss, Dublin, CA; RTVue, Optovue, Fremont, CA; and Spectralis, Heidelberg Engineering, Heidelberg, Germany). All the images were processed with the signal normalization. A set of images formed a questionnaire with 24 pairs of cross-sectional images from each eye with any combination of the three SD-OCT devices either both pre- or postsignal normalization. Observers were asked to evaluate the similarity of the two displayed images based on the image appearance. The effects on reducing the differences in image appearance before and after processing were analyzed. RESULTS: Twenty-nine researchers familiar with OCT images participated in the survey. Image similarity was significantly improved after signal normalization for all three combinations (P