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Myopia and glaucoma are both increasing in prevalence and are linked by an unknown mechanism as many epidemiologic studies have identified moderate to high myopia as an independent risk factor for glaucoma. Myopia and glaucoma are both chronic conditions that lead to connective tissue remodeling within the sclera and optic nerve head. The mechanobiology underlying connective tissue remodeling differs substantially between both diseases, with different homeostatic control mechanisms. In this article, we discuss similarities and differences between connective tissue remodeling in myopia and glaucoma; selected multi-scale mechanisms that are thought to underlie connective tissue remodeling in both conditions; how asymmetric remodeling of the optic nerve head may predispose a myopic eye for pathological remodeling and glaucoma; and how neural tissue deformations may accumulate throughout both pathologies and increase the risk for mechanical insult of retinal ganglion cell axons.

Purpose To find genetic contributions to glaucoma in African Americans. Design Cross-sectional, case-control study. Participants One thousand eight hundred seventy-five primary open-angle glaucoma (POAG) patients and 1709 controls, self-identified as being of African descent (AD), from the African Descent and Glaucoma Evaluation Study (ADAGES) III and Wake Forest School of Medicine. Methods MegaChip genotypes were imputed to Thousand Genomes data. Association of single nucleotide polymorphisms (SNPs) with POAG and advanced POAG was tested by linear mixed model correcting for relatedness and population stratification. Genetic risk scores were tested by receiver operator characteristic curves (ROC-AUCs). Main Outcome Measures Primary open-angle glaucoma defined by visual field loss without other nonocular conditions (n = 1875). Advanced POAG was defined by age-based mean deviation of visual field (n = 946). Results Eighteen million two hundred eighty-one thousand nine hundred twenty SNPs met imputation quality of r2 > 0.7 and minor allele frequency > 0.005. Association of a novel locus, EN04, was observed for advanced POAG (rs185815146 β, 0.36; standard error, 0.065; P Conclusions A novel association with advanced POAG in the EN04 locus was identified putatively in persons of AD. In addition to this finding, this genome-wide association study in POAG patients of AD contributes to POAG genetics by identification of novel signals in prior loci (9p21), as well as advancing the fine mapping of regions because of shorter average LD (FNDC3B). Although not useful without confirmation and clinical trials, the use of genetic risk scores demonstrated that considerable AD-specific genetic information remains in these data.

PURPOSE:To describe the study protocol and baseline characteristics of the African Descent and Glaucoma Evaluation Study (ADAGES) III. DESIGN:Cross-sectional, case-control study. PARTICIPANTS:Three thousand two hundred sixty-six glaucoma patients and control participants without glaucoma of African or European descent were recruited from 5 study centers in different regions of the United States. METHODS:Individuals of African descent (AD) and European descent (ED) with primary open-angle glaucoma (POAG) and control participants completed a detailed demographic and medical history interview. Standardized height, weight, and blood pressure measurements were obtained. Saliva and blood samples to provide serum, plasma, DNA, and RNA were collected for standardized processing. Visual fields, stereoscopic disc photographs, and details of the ophthalmic examination were obtained and transferred to the University of California, San Diego, Data Coordinating Center for standardized processing and quality review. MAIN OUTCOME MEASURES:Participant gender, age, race, body mass index, blood pressure, history of smoking and alcohol use in POAG patients and control participants were described. Ophthalmic measures included intraocular pressure, visual field mean deviation, central corneal thickness, glaucoma medication use, or past glaucoma surgery. Ocular conditions, including diabetic retinopathy, age-related macular degeneration, and past cataract surgery, were recorded. RESULTS:The 3266 ADAGES III study participants in this report include 2146 AD POAG patients, 695 ED POAG patients, 198 AD control participants, and 227 ED control participants. The AD POAG patients and control participants were significantly younger (both, 67.4 years) than ED POAG patients and control participants (73.4 and 70.2 years, respectively). After adjusting for age, AD POAG patients had different phenotypic characteristics compared with ED POAG patients, including higher intraocular pressure, worse visual acuity and visual field mean deviation, and thinner corneas (all P < 0.001). Family history of glaucoma did not differ between AD and ED POAG patients. CONCLUSIONS:With its large sample size, extensive specimen collection, and deep phenotyping of AD and ED glaucoma patients and control participants from different regions in the United States, the ADAGES III genomics study will address gaps in our knowledge of the genetics of POAG in this high-risk population.

Purpose Recent retrospective clinical studies and animal experiments have suggested that cerebrospinal fluid pressure (CSFP) is important in glaucoma, acting through the translaminar pressure (TLP = IOP - CSFP), which directly affects the optic nerve head. In this study, IOP and intracranial pressure (ICP; a surrogate of CSFP) were measured at various body positions to quantify the determinants of TLP. Methods We have developed an implantable wireless pressure telemetry system based on a small piezoelectric sensor with low temporal drift. Telemetry transducers were placed in the anterior chamber to measure IOP and in the brain parenchyma at eye height to measure ICP. IOP was calibrated against anterior cannulation manometry, and ICP/CSFP was calibrated against an intraparenchymal Codman ICP Express microsensor. We measured IOP, ICP, and TLP = IOP - ICP continuously at 200 Hz in three male nonhuman primates (NHPs) in three trials; pressures were then averaged for 30 seconds per body position. Relative change of IOP, ICP, and TLP from the supine (baseline) position to the seated, standing, and inverted positions were quantified. Results TLP changed significantly and instantaneously from the supine to seated (+14 mm Hg), supine to standing (+13 mm Hg) and supine to inverted (-12 mm Hg) positions (P < 0.05). There was no significant TLP change for supine to prone. ICP showed greater relative change than IOP. Conclusions TLP change due to body position change is driven more by ICP/CSFP than IOP. IOP, ICP, and TLP variability, coupled with telemetry, should allow us to test the hypotheses that IOP, ICP, or TLP fluctuations contribute independently to glaucoma onset or progression.

Importance While 6-month data are available regarding spaceflight-associated neuro-ocular syndrome, manned missions for 1 year and beyond are planned, warranting evaluation for spaceflight-associated neuro-ocular syndrome beyond 6 months. Objective To determine if the manifestation of spaceflight-associated neuro-ocular syndrome worsens during International Space Station missions exceeding the present 4- to 6-month duration. Design, Setting, and Participants The One-Year Mission Study used quantitative imaging modalities to investigate changes in ocular structure in 2 crew members who completed a 1-year–long spaceflight mission. This study investigated the ocular structure of crew members before, during, and after their mission on the International Space Station. Two crew members participated in this study from March 2015 to September 2016. Analysis began in March 2015 and ended in May 2020. Exposures Crew members were tested before, during, and up to 1 year after spaceflight. Main Outcomes and Measures This study compares ocular changes (peripapillary retinal edema, axial length, anterior chamber depth, and refraction) in two 1-year spaceflight mission crew members with cohort crew members from a 6-month mission (n = 11). Minimum rim width (the shortest distance between Bruch membrane opening and the internal limiting membrane) and peripapillary total retinal thickness were measured using optical coherence tomography. Results Both crew members were men. Minimum rim width and total retinal thickness increased in both participants throughout the duration of spaceflight exposure to the maximal observed change from preflight (minimum rim width: participant 1, 561 [+149 from preflight] μm at flight day 270; participant 2, 539 [+56 from preflight] μm at flight day 270; total retinal thickness: participant 1, 547 [+135 from preflight] μm at flight day 90; participant 2, 528 [+45 from preflight] μm at flight day 210). Changes in peripapillary choroid engorgement, axial length, and anterior chamber depth appeared similar between the 1-year mission participants and a 6-month mission cohort. Conclusions and Relevance This report documents the late development of mild optic disc edema in 1 crew member and the progressive development of choroidal folds and optic disc edema in another crew member over the duration of 1 year in low Earth orbit aboard the International Space Station. Previous reports characterized the ocular risk associated with 4 to 6 months of spaceflight. As future spaceflight missions are planned to increase in duration and extend beyond low Earth orbit, further observation of astronaut ocular health on spaceflight missions longer than 6 months in duration may be warranted.

Many experiments have documented the response of intraocular pressure (IOP) to postural change. External forces caused by gravitational orientation change produce a dynamic response that is encountered every day during normal activities. Tilting the body at a small downward angle is also relevant to studying the effects of hypogravity (spaceflight), including ocular changes. We examined data from 36 independent datasets from 30 articles on IOP response to postural change, representing a total population of 821 subjects (≥1173 eyes) with widely varying initial and final postures. We confirmed that IOP was well predicted by a simple quantity, namely the hydrostatic pressure at the level of the eye, although the dependence was complex (nonlinear). Our results show that posturally induced IOP change can be explained by hydrostatic forcing plus an autoregulatory contribution that is dependent on hydrostatic effects. This study represents data from thousands of IOP measurements and provides insight for future studies that consider postural change in relation to ocular physiology, intraocular pressure, ocular blood flow and aqueous humor dynamics.

Spontaneous retinal venous pulsations (SRVPs), pulsations of branches of the central retinal vein, are affected by intraocular pressure (IOP) and intracranial pressure (ICP) and thus convey potentially-useful information about ICP. However, the exact relationship between SRVPs, IOP, and ICP is unknown. It is not easily feasible to study this relationship in humans, necessitating the use of an animal model. We here propose tree shrews as a suitable animal model to study the complex relationship between SRVPs, IOP, and ICP. Tree shrew SRVP incidence was determined in a population of animals. Following validation of a modified IOP control system to accurately and quickly control IOP, IOP and/or ICP were manipulated in two tree shrews with SRVPs and the effects on SRVP properties were quantified. SRVPs were present in 75% of tree shrews at physiologic IOP and ICP. Altering IOP or ICP produced changes in tree shrew SRVP properties; specifically, increasing IOP caused SRVP amplitude to increase, while increasing ICP caused SRVP amplitude to decrease. In addition, a higher IOP was necessary to generate SRVPs at a higher ICP than at a lower ICP. SRVPs occur with a similar incidence in tree shrews as in humans, and tree shrew SRVPs are affected by changes in IOP and ICP in a manner qualitatively similar to that reported in humans. In view of anatomic similarities, tree shrews are a promising animal model system to further study the complex relationship between SRVPs, IOP, and ICP.

To describe the first known case of Bacteroides spp. related blebitis, keratitis, and endophthalmitis following uncomplicated trabeculectomy.This was a case report and literature review.A 63-year-old immunocompetent white male underwent uncomplicated trabeculectomy of his right eye. Two weeks later, a blebitis with adjacent keratitis was diagnosed, progressing over several days to endophthalmitis despite hourly topical fortified antibiotic therapy. Although gram stain and culture of the bleb surface, a conjunctival suture, the aqueous humor, and the vitreous were negative, topical real-time quantitative polymerase chain reaction testing disclosed the presence of Bacteroides spp. Following treatment with topical and intravitreal clindamycin and intravenous meropenem, all clinical evidence of infection resolved. Best spectacle-corrected visual acuity improved to 20/25 (0.8) subsequent to combined cataract extraction, intraocular lens implantation, and pars plana vitrectomy for persistent vitreous debris.Bacteroides may be a rare cause of postoperative blebitis, keratitis, and endophthalmitis. A favorable outcome may be attained, provided that an accurate diagnosis and effective treatment can be provided, which may be facilitated by real-time quantitative polymerase chain reaction in select cases.

Purpose To evaluate the effect of scleral crosslinking (SXL) on slowing experimental progressive myopia in tree shrew eyes using sub-Tenon's injections of genipin (GEN) at different concentrations and number of injections. Methods Three or five sub-Tenon's injections of GEN at 0 mM (sham), 10 mM, or 20 mM were performed in one eye every other day starting at 18 days of visual experience. Form deprivation (FD) myopia was induced in the injected eye between 24 and 35 days of visual experience; the fellow eye served as control. Tree shrews were randomly assigned to five experimental groups: FD (n = 8); FD + 5 × sham injections (n = 6); FD + 3 × GEN injections at 10 mM (n = 6) and 20 mM (n = 6); and FD + 5 × GEN injections at 20 mM (n = 6). Refractive state and ocular dimensions were measured daily. Results Compared with the FD group, the sham-injected group showed a transient effect on slowing vitreous chamber elongation. With increasing GEN dose, SXL had an increasing treatment effect on slowing vitreous chamber elongation and myopia progression. In addition, SXL led to a dose-dependent shortening of the aqueous chamber depth and corneal thickening. Lens thickening was observed in the group with the highest concentration. Conclusions We have shown that SXL using GEN can slow axial elongation and myopia progression in tree shrews. The extent of this treatment effect was dose dependent. Several unexpected effects were observed (corneal thickening, decrease of the anterior chamber depth, and lens thickening), which require further optimization of the GEN delivery approach before clinical consideration. Translational relevance The results of this preclinical study suggest that scleral crosslinking using genipin can slow myopia progression.

Purpose Recent retrospective clinical and animal studies suggest that cerebrospinal fluid pressure (CSFP) is important in glaucoma pathogenesis. Intraocular pressure (IOP) and CSFP are the driving components of translaminar pressure (TLP = IOP – CSFP), which acts across the lamina cribrosa (LC) thickness to create the translaminar pressure gradient (TLPG = TLP/LC thickness). Methods We developed an implantable wireless telemetry system based on a small piezoelectric sensor with low temporal drift. IOP, measured in the anterior chamber, and intracranial pressure (ICP), measured in the brain parenchyma (as a surrogate for CSFP) were measured at 200 Hz in three male rhesus macaques (nonhuman primates, NHPs) on a 10% duty cycle (15 seconds of every 150-second period). Three-dimensional LC thickness was autosegmented as the mean thickness of the visible hyperreflective band in 48 radial spectral-domain optical coherence tomography b-scans centered on the optic nerve head. Results Results indicated the rank order of IOP, ICP, TLP, and TLPG for waking, sleeping, and 24-hour periods averaged across all days. NHP 150110 had the highest IOP and ICP in all periods; however, it had the lowest TLPG in all periods due to its relatively thick LC. The other two NHPs showed similar shifts in the rank order of possible glaucoma risk factors. Conclusions IOP is the only modifiable and readily measurable pressure-based risk factor for glaucoma. However, other potential risk factors such as ICP, TLP, and TLPG, as well as their rank-order patterns, differed compared to IOP across subjects, demonstrating that a comprehensive view of relevant risk factors is warranted. Translational Relevance Future studies should consider including CSFP, TLP, and TLPG in addition to IOP as potential risk factors when assessing eye-specific glaucoma susceptibility.

Purpose To characterize ocular perfusion pressure (OPP) fluctuations with continuous telemetry over 24-hour periods across multiple days in nonhuman primates (NHPs) to test the hypotheses that OPP differs among NHPs and that the diurnal cycle of OPP is characterized by low OPP during sleep. Methods We have developed and validated two implantable radiotelemetry systems that allow continuous measurement of intraocular pressure (IOP), arterial blood pressure (BP), and OPP up to 500 Hz. OPP was measured unilaterally in 12 male NHPs for periods of 38 to 412 days. IOP transducers were calibrated directly via anterior chamber manometry, and OPP was calculated continuously as central retinal artery BP minus IOP. OPP data were corrected for signal drift between calibrations and averaged hourly. Results OPP varied widely among animals, with daily averages ranging from ∼47 to 65 mm Hg. In eight of 12 NHPs, OPP was significantly lower during sleep compared to waking hours. In three animals, the diurnal cycle was reversed and OPP was significantly higher during sleep (P < 0.05), and one NHP showed no diurnal cycle. Day-to-day OPP variability within NHPs was the largest source of overall OPP variability, even larger than the differences between NHPs. Average daily OPP showed an unexplained ∼32-day cyclic pattern in most NHPs. Conclusions Average OPP varied widely and exhibited differing diurnal cycles in NHPs, a finding that matches those of prior patient studies and indicates that OPP studies in the NHP model are appropriate. Infrequent snapshot measurements of either IOP or BP are insufficient to capture true IOP, BP, and OPP and their fluctuations.

Purpose Recent retrospective clinical studies and animal experiments have suggested that cerebrospinal fluid pressure (CSFP) is important in glaucoma pathogenesis. Intraocular pressure (IOP) and CSFP are the driving components of the translaminar pressure (TLP), which directly effects the optic nerve head. This study measured the diurnal cycle of TLP using continuous wireless telemetry in nonhuman primates (NHPs), a common animal model of glaucoma. Methods We have developed an implantable wireless telemetry system based on a small piezoelectric pressure transducer with low drift. Unilateral IOP was measured in the anterior chamber of the eye, and intracranial pressure (ICP, a surrogate measure of CSFP) was measured in the brain parenchyma in four awake, behaving NHPs for periods of 22 to 281 days. IOP and ICP telemetry transducers were calibrated with direct pressure measurements in the eye (every 2 weeks) and brain (monthly). TLP was quantified in real time as IOP-ICP, and hourly means of IOP, ICP, and TLP were analyzed. Results Results show that mean ICP is significantly higher by an average of 4.8 ± 0.8 mmHg during sleeping hours in NHPs (P < 0.01). IOP showed a small but significant nocturnal elevation in two of four animals despite NHPs sleeping upright (P < 0.05). TLP was significantly lower during sleep (7.1 ± 0.6 mmHg; P < 0.01) than when the animals were awake and active (11.0 ± 0.9 mmHg), driven primarily by the large increase in ICP during sleep. Conclusions The 56% increase in TLP during waking hours in NHPs matches the increase in TLP due to postural change from supine to upright reported previously in humans.

Purpose To study the effect and time course of body position changes on IOP in nonhuman primates. Methods We recorded continuous bilateral IOP measurements with a wireless telemetry implant in three rhesus macaques in seven different body positions. IOP measurements were acquired in the seated-upright, standing, prone, supine, right and left lateral decubitus positions (LDPs), and head-down inverted positions. Continuous IOP was recorded for 90 seconds in each position before returning to a supine reference position until IOP stabilized; measurements were averaged after IOP stabilized at each position. Results Head-down inversion increased IOP an average of 8.9 mm Hg, compared to the supine reference. In the LDP, IOP decreased an average of 0.5 mm Hg in the nondependent eye (i.e., the higher eye), while the fellow dependent (i.e., lower) eye increased an average of 0.5 mm Hg, compared to supine reference. Standing and seated positions decreased IOP 1.5 and 2.2 mm Hg, respectively, compared with supine reference. IOP changes occurred within 4 to 15 seconds of a body position change, and timing was affected by the speed at which body position was changed. Compared to the IOP in the supine position, the IOP in the inverted, prone, and seated positions was significantly different (P = 0.0313 for all). The IOP in the standing position was not statistically different from the IOP in the supine position (P = 0.094). In addition, the IOP was significantly different between the nondependent eye and the dependent eye in the LDPs compared to the supine position (P = 0.0313). Conclusions Body position has a significant effect on IOP and those changes persist over time.

Background Although the hypothalamic orexin system is known to regulate appetitive behaviors and promote wakefulness and arousal (Sakurai, 2007 [56] ), this system may also be important in adaptive and pathological anxiety/stress responses (Suzuki et al., 2005 [4]). In a recent study, we demonstrated that CSF orexin levels were significantly higher in patients experiencing panic attacks compared to non-panicking depressed subjects (Johnson et al., 2010 [9]). Furthermore, genetically silencing orexin synthesis or blocking orexin 1 receptors attenuated lactate-induced panic in an animal model of panic disorder. Therefore, in the present study, we tested if orexin (ORX) modulates panic responses and brain pathways activated by two different panicogenic drugs. Methods We conducted a series of pharmacological, behavioral, physiological and immunohistochemical experiments to study the modulation by the orexinergic inputs of anxiety behaviors, autonomic responses, and activation of brain pathways elicited by systemic injections of anxiogenic/panicogenic drugs in rats. Results We show that systemic injections of two different anxiogenic/panicogenic drugs (FG-7142, an inverse agonist at the benzodiazepine site of the GABA A receptor, and caffeine, a nonselective competitive adenosine receptor antagonist) increased c-Fos induction in a specific subset of orexin neurons located in the dorsomedial/perifornical (DMH/PeF) but not the lateral hypothalamus. Pretreating rats with an orexin 1 receptor antagonist attenuated the FG-7142-induced anxiety-like behaviors, increased heart rate, and neuronal activation in key panic pathways, including subregions of the central nucleus of the amygdala, bed nucleus of the stria terminalis, periaqueductal gray and in the rostroventrolateral medulla. Conclusion Overall, the data here suggest that the ORX neurons in the DMH/PeF region are critical to eliciting coordinated panic responses and that ORX1 receptor antagonists constitute a potential novel treatment strategy for panic and related anxiety disorders. The neural pathways through which ORX1 receptor antagonists attenuate panic responses involve the extended amygdala, periaqueductal gray, and medullary autonomic centers.

Purpose To assess the prevalence of subretinal drusenoid deposits (SDD) in older adults with healthy maculas and early and intermediate age-related macular degeneration (AMD) using multimodal imaging. Design Cross-sectional study. Participants A total of 651 subjects aged ≥60 years enrolled in the Alabama Study of Early Age-Related Macular Degeneration from primary care ophthalmology clinics. Methods Subjects were imaged using spectral domain optical coherence tomography (SD OCT) of the macula and optic nerve head (ONH), infrared reflectance, fundus autofluorescence, and color fundus photographs (CFP). Eyes were assessed for AMD presence and severity using the Age-Related Eye Disease Study (AREDS) 9-step scale. Criteria for SDD presence were identification on ≥1 en face modality plus SD OCT or on ≥2 en face modalities if absent on SD OCT. Subretinal drusenoid deposits were considered present at the person level if present in 1 or both eyes. Main Outcome Measures Prevalence of SDD in participants with and without AMD. Results Overall prevalence of SDD was 32% (197/611), with 62% (122/197) affected in both eyes. Persons with SDD were older than those without SDD (70.6 vs. 68.7 years, P = 0.0002). Prevalence of SDD was 23% in subjects without AMD and 52% in subjects with AMD ( P Conclusions Subretinal drusenoid deposits are present in approximately one quarter of older adults with healthy maculae and in more than half of persons with early to intermediate AMD, even by stringent criteria. The prevalence of SDD is strongly associated with AMD presence and severity and increases with age, and its retinal topography including peripapillary involvement resembles that of rod photoreceptors. Consensus on SDD detection methods is recommended to advance our knowledge of this lesion and its clinical and biologic significance.

To study the health profiles and behavioral differences between primary open angle glaucoma (POAG) and normal tension glaucoma (NTG) patients.Confidential mail survey of ICD-9 defined POAG (n = 277) and NTG (n = 116) patients was carried out to collect information regarding age, gender, height, weight, waist circumference, blood pressure (BP), medications [prescription (Rx) and over the counter (OTC)], education, and the Short Health Anxiety Inventory (SHAI).NTG patients (59/116) were significantly more likely to respond to the survey than POAG patients (43/277), p = 0.0001, and to have obtained college level education (70% vs. 42%), p = 0.003. Body weight, waist circumference, body mass index, systolic BP, pulse pressure, and ratio of prescription medications to OTC medications were significantly lower in the NTG group (p 0.0001). The SHAI score, mean age, and diastolic BP were not different between the two groups. A subgroup analysis of college-educated patients in both groups revealed persisting significant differences in waist circumference, systolic BP, and ratio of Rx to OTC medications.NTG patients do not have significantly greater health anxiety than POAG patients. NTG patients are more likely to have lower BMI, systolic BP, and ratio of Rx to OTC medications than POAG patients. The pilot nature of this study limits generalizability of these findings. Larger studies confirming these findings and elucidating the role of refractive error and medical history on such differences are needed.

Purpose Choroid geometry and swelling have been proposed to contribute to ocular pathologies. Thus, it is important to understand how the choroid may impact the optic nerve head (ONH) biomechanical environment. We developed a finite element model to study how acute choroidal swelling and choroid geometry affect ONH deformation. Methods We developed two geometric models of the ONH: one with a "blunt" choroidal insertion and another with a "tapered" choroid insertion. We examined how choroidal volume changes (2.1-14.2 μL, estimated to occur during the ocular pulse) impact biomechanical strain in three tissue regions: the prelaminar neural tissue, lamina cribrosa, and retrolaminar neural tissue. Then, we performed a sensitivity analysis to understand how variation in ONH pressures, tissue material properties, and choroidal swelling influenced the peak tissue strains. Results Choroidal swelling in the blunt choroid geometry had a large impact on the strains in the prelaminar neural tissue, with magnitudes comparable to those expected to occur due to an IOP of 30 mm Hg. Choroidal swelling in the tapered choroid geometry also affected strains but to a lesser extent compared to the blunt geometry. A sensitivity analysis confirmed that choroidal swelling was more influential on prelaminar neural tissue strains in the blunt choroid geometry. Conclusions Choroid anatomy and swelling can interact to play an important role in prelaminar neural tissue deformation. These findings suggest that the choroid may play an important, and previously unappreciated, role in ONH biomechanics, and motivate additional research to better define the in vivo effects of choroidal volume change.

Purpose Primates and rodents are used widely as animal models of glaucoma, but each has significant limitations. Researchers need additional animal models that closely resemble the relevant anatomy and pathologic features of the human disease to more quickly advance research. We validate a novel glaucoma animal model in tree shrews (Tupaia belangeri). Methods Experimental glaucoma was induced in adult tree shrews (n = 8) by injecting 50 μL of a 25 mg/mL ferromagnetic bead solution into the anterior chamber. Beads were directed into the iridocorneal angle with a magnet to impede aqueous outflow. Animals were followed for 3 months with weekly IOP measurements and biweekly spectral domain optical coherence tomography (SD-OCT) images of the optic nerve head. Histopathology of the optic nerve and optic nerve axon counts were completed at the end of the study. Results The 12-week average mean IOP was 22.7 ± 3.6 and 8.6 ± 2.9 mm Hg in the treated and control eyes, respectively. Longitudinal analysis showed significant retinal nerve fiber layer (RNFL) thinning throughout the study. Axon counts were significantly reduced (59.7%) in treated versus control eyes. SD-OCT imaging showed cupping and posterior displacement of the lamina cribrosa in glaucomatous eyes. RNFL thickness and optic nerve axon counts were reduced consistent with IOP elevation. Optic nerves demonstrated histopathology consistent with glaucomatous optic neuropathy. Conclusions Tree shrews with experimental glaucoma show key pathologic characteristics of the human disease. The tree shrew model of glaucoma has the potential to help researchers accelerate our understanding of glaucoma pathophysiology.

Pathologic changes in intracranial pressure (ICP) are commonly observed in a variety of medical conditions, including traumatic brain injury, stroke, brain tumors, and glaucoma. However, current ICP measurement techniques are invasive, requiring a lumbar puncture or surgical insertion of a cannula into the cerebrospinal fluid (CSF)-filled ventricles of the brain. A potential alternative approach to ICP measurement leverages the unique anatomy of the central retinal vein, which is exposed to both intraocular pressure (IOP) and ICP as it travels inside the eye and through the optic nerve; manipulating IOP while observing changes in the natural pulsations of the central retinal vein could potentially provide an accurate, indirect measure of ICP. As a step toward implementing this technique, we describe the design, fabrication, and characterization of a system that is capable of manipulating IOP in vivo with

Emotional stress provokes a stereotyped pattern of autonomic and endocrine changes that is highly conserved across diverse mammalian species. Nearly 50 years ago, a specific region of the hypothalamus, the hypothalamic defense area, was defined by the discovery that electrical stimulation in this area evoked changes that replicated this pattern. Attention later shifted to the hypothalamic paraventricular nucleus (PVN) owing to (1) elucidation of its role as the final common pathway mediating activation of the hypothalamic-pituitary-adrenal (HPA) axis, a defining feature of the stress response and (2) the finding that the PVN was the principal location of hypothalamic neurons that project directly to spinal autonomic regions. Consequently, a primary role for the PVN as the hypothalamic center integrating the autonomic and endocrine response to stress was inferred. However, our findings indicate that neurons in the nearby dorsomedial hypothalamus (DMH)--a region originally included in the hypothalamic defense area--and not in the PVN play a key role in the cardiovascular changes associated with emotional or exteroceptive stress. Indeed, excitation of neurons in the parvocellular PVN and consequent recruitment of the HPA axis that occurs in exteroceptive stress is also signaled from the DMH. Thus, the DMH may represent a higher order hypothalamic center responsible for integrating autonomic, endocrine and even behavioral responses to emotional stress.

Purpose Visual impairment and intracranial pressure (VIIP) syndrome is a health concern for long-duration spaceflight, and a proposed risk factor is elevation of intracranial pressure (ICP). Our goal was to use finite element modeling to simulate how elevated ICP and interindividual differences affect tissue deformation within the optic nerve head (ONH). Methods We considered three ICP conditions: the upright and supine position on earth and an elevated ICP assumed to occur in chronic microgravity. Within each condition we used Latin hypercube sampling to consider a range of pressures and ONH tissue mechanical properties, determining the influence of each input on the following outcome measures: peak strains in the prelaminar tissue, lamina cribrosa, and retrolaminar optic nerve. Elevated strains can alter cell phenotype and induce tissue remodeling. Results Elevating ICP increased the strains in the retrolaminar optic nerve. Variations in IOP, ICP, and in optic nerve and lamina cribrosa stiffness had the strongest influence on strains within the ONH. We predicted that 5% to 47% of individuals in microgravity would experience peak strains in the retrolaminar optic nerve larger than expected on earth. Having a soft optic nerve or pia mater and elevated ICP were identified as risk factors for these "extreme" strains. Conclusions Intracranial pressure and mechanical properties of the ONH influence the risk for experiencing extreme strains in the retrolaminar optic nerve. These extreme strains may activate mechanosensitive cells that induce tissue remodeling and are a risk factor for the development of VIIP. Future studies must also consider variations in ONH anatomy.

Acute hypercapnia (elevated arterial CO(2)/H(+)) is a suffocation signal that is life threatening and rapidly mobilizes adaptive changes in breathing and behavioral arousal in order to restore acid-base homeostasis. Severe hypercapnia, seen in respiratory disorders (eg, asthma or bronchitis, chronic obstructive pulmonary disease (COPD)), also results in high anxiety and autonomic activation. Recent evidence has demonstrated that wake-promoting hypothalamic orexin (ORX: also known as hypocretin) neurons are highly sensitive to local changes in CO(2)/H(+), and mice lacking prepro-ORX have blunted respiratory responses to hypercapnia. Furthermore, in a recent clinical study, ORX-A, which crosses blood-brain barrier easily, was dramatically increased in the plasma of patients with COPD and hypercapnic respiratory failure. This is consistent with a rodent model of COPD where chronic exposure to cigarette smoke led to a threefold increase in hypothalamic ORX-A expression. In the present study, we determined the role of ORX in the anxiety-like behavior and cardiorespiratory responses to acute exposure to a threshold panic challenge (ie, 20% CO(2)/normoxic gas). Exposing conscious rats to such hypercapnic, but not atmospheric air, resulted in respiratory, pressor, and bradycardic responses, as well as anxiety-like behavior and increased cellular c-Fos responses in ORX neurons. Systemically, pre-treating rats with a centrally active ORX1 receptor antagonist (30 mg/kg SB334867) attenuated hypercapnic gas-induced pressor and anxiety responses, without altering the robust bradycardia response, and only attenuated breathing responses at offset of the CO(2) challenge. Our results show that the ORX system has an important role in anxiety and sympathetic mobilization during hypercapnia. Furthermore, ORX1 receptor antagonists may be a therapeutic option rapidly treating increased anxiety and sympathetic drive seen during panic attacks and in hypercapnic states such as COPD.

Disinhibition of neurons in the region of the dorsomedial hypothalamus (DMH) elicits sympathetically mediated tachycardia in rats through activation of the brain stem raphe pallidus (RP), and this same mechanism appears to be largely responsible for the increases in heart rate (HR) seen in air jet stress in this species. Neurons projecting to the RP from the DMH are said to be concentrated in a specific subregion, the dorsal hypothalamic area (DA). Here, we examined the hypothesis that the location of RP-projecting neurons in the DA correspond to the sites at which microinjection of bicuculline methiodide (BMI) evokes the greatest increases in HR. To determine the distribution of RP-projecting neurons in the DA, cholera toxin B was injected in the RP in four rats. A consistent pattern of retrograde labeling was seen in every rat. In the hypothalamus, RP-projecting neurons were most heavily concentrated midway between the mammillothalamic tract and the dorsal tip of the third ventricle dorsal to the dorsomedial hypothalamic nucleus ∼3.30 mm caudal to bregma. In a second series of experiments, the HR response to microinjections of BMI (2 pmol/5 nl; n = 76) was mapped at sites in the DA and surrounding areas in 22 urethane-anesthetized rats. All injection sites were located from 2.56 to 4.16 mm posterior to bregma, and the microinjections that evoked the largest increase in HR (i.e., >100 beats/min in some instances) were located in a region where RP-projecting neurons were most densely concentrated. Thus RP-projecting neurons in the DA may mediate DMH-induced tachycardia and thus play a role in stress-induced cardiac stimulation.

Sympathetically mediated tachycardia is a characteristic feature of the physiological response to emotional or psychological stress in mammals. Activation of neurons in the region of the dorsomedial hypothalamus appears to play a key role in the integration of this response. Tachycardia evoked by chemical stimulation of the dorsomedial hypothalamus can be suppressed by microinjection of the GABA(A) receptor agonist and neuronal inhibitor muscimol into the raphe pallidus (RP). Therefore, we tested the hypothesis that neuronal excitation in the RP mediates tachycardia seen in experimental air stress in rats. Microinjection of the GABA(A) receptor antagonist bicuculline methiodide (BMI) into the RP evoked increases in heart rate. At the same sites, microinjection of muscimol (80 pmol (100 nl)(-1)) had no effect on heart rate under baseline conditions but virtually abolished air stress-induced tachycardia, while microinjection of lower doses (10 or 20 pmol) produced transient but clear suppression. Microinjection of muscimol at sites outside the RP had no effect on stress-induced tachycardia, although modest suppression was apparent after injection at two sites within 500 microm of the RP. In another series of experiments, microinjection of muscimol (80 pmol (100 nl)(-1)) into the RP failed to influence the changes in heart rate produced by baroreceptor loading or unloading. These findings indicate that activity of neurons in the RP plays a previously unrecognized role in the generation of stress-induced tachycardia.

Activation of neurons in the region of the dorsomedial hypothalamus (DMH) appears to generate the sympathetically mediated tachycardia seen in experimental stress in rats. The purpose of this study was to assess the role of neurons in the area of the medullary raphe pallidus (RP) in the tachycardia caused by stimulation of the DMH. The cardiovascular response to microinjection of the GABA(A) receptor antagonist bicuculline methiodide (BMI) 10 pmol (100 nl)(-1) into the DMH was assessed before, and after, injection of the GABA(A) receptor agonist muscimol 80 pmol (100 nl)(-1) or saline vehicle 100 nl into the RP in urethane-anaesthetized rats. Tachycardia evoked by microinjection of BMI into the DMH was mimicked by microinjection of BMI 30 pmol (75 nl)(-1) into the RP. This DMH-induced tachycardia was markedly suppressed after injection of muscimol into the RP, but the response was unaffected by injection of saline into the same region. Thus, DMH-induced tachycardia is mediated through activation of neurons in the area of the RP, suggesting that these neurons may play a previously unrecognized role in stress-induced cardiac stimulation.

PURPOSE. Intraocular pressure (IOP) fluctuation has recently been identified as a risk factor for glaucoma progression. Further, decreases in intracranial pressure (ICP), with postulated increases in the translaminar pressure gradient across the lamina cribrosa, has been reported in glaucoma patients. We hypothesized that circadian fluctuations in IOP and the translaminar pressure gradient are influenced, at least in part, by central autonomic regulatory neurons within the dorsomedial and perifornical hypothalamus (DMH/PeF). This study examined whether site-directed chemical stimulation of DMH/PeF neurons evoked changes in IOP, ICP, and the translaminar pressure gradient. METHODS. The GABAA receptor antagonist bicuculline methiodide (BMI) was stereotaxically microinjected into the DMH/PeF region of isoflurane-anesthetized male Sprague-Dawley rats (n ¼ 19). The resulting peripheral cardiovascular (heart rate [HR] and mean arterial pressure [MAP]), IOP, and ICP effects were recorded and alterations in the translaminar pressure gradient calculated. RESULTS. Chemical stimulation of DMH/PeF neurons evoked significant increases in HR (þ69.3 6 8.5 beats per minute); MAP (þ22.9 6 1.6 mm Hg); IOP (þ7.1 6 1.9 mm Hg); and ICP (þ3.6 6 0.7 mm Hg) compared with baseline values. However, the peak IOP increase was significantly delayed compared with ICP (28 vs. 4 minutes postinjection), resulting in a dramatic translaminar pressure gradient fluctuation. CONCLUSIONS. Chemical stimulation of DMH/PeF neurons evokes substantial increases in IOP, ICP, and the translaminar pressure gradient in the rat model. Given that the DMH/PeF neurons may be a key effector pathway for circadian regulation of autonomic tone by the suprachiasmatic nucleus, these findings will help elucidate novel mechanisms modulating circadian fluctuations in IOP and the translaminar pressure gradient. (Invest Ophthalmol Vis Sci. 2012; 53:7328‐7335) DOI:10.1167/iovs.12-10632