Intracranial pressure modulates aqueous humour dynamics of the eye.
ABSTRACT: KEY POINTS:An elevation in intracranial pressure (ICP) lowers conventional outflow facility (increases aqueous outflow resistance) of rat eyes. The reduction in outflow facility correlates with an increase in intraocular pressure (IOP). The effect of ICP elevation on outflow facility and IOP is blocked by TTX. The results indicate that aqueous humour dynamics is modulated by ICP-driven neural feedback from the brain. This feedback mechanism may act to stabilize translaminar pressure across the optic nerve head and may provide a new avenue for glaucoma therapy. ABSTRACT:While intraocular pressure (IOP) is a well-known risk factor for glaucoma, intracranial pressure (ICP) is attracting heightened interest because of its influence on optic nerve head biomechanics. Studies have shown that ICP can have marked impacts on posterior eye health by modifying the translaminar pressure gradient across the optic nerve. There is also growing evidence that IOP and ICP may be interconnected, although the mechanism of their putative interaction is unknown. We sought to test the hypothesis that ICP modulates IOP by altering aqueous humour dynamics. The anterior chamber and lateral ventricle of anaesthetized Brown-Norway rats were cannulated with fine-gauge needles connected to a programmable pump and saline reservoir, respectively. ICP was manipulated by varying reservoir height, and eye outflow facility (C) was determined from the pump flow rate required to hold IOP at different levels. C was 22 ± 4 nl/min/mmHg at resting ICP and 13 ± 3 nl/min/mmHg when ICP was raised 15 mmHg, a reduction of 41 ± 13% (n = 18). The decrease in outflow facility was independent of blood pressure, reversible, scaled with ICP elevation and correlated with increases in resting IOP. It was physiological in origin because C returned to baseline values after the rats were killed and corneal application of TTX though ICP remained elevated. These results indicate that a neural feedback mechanism driven by ICP regulates conventional outflow facility in rats. The mechanism may protect the eye from translaminar pressure swings and may offer a new target for glaucoma treatment.
Project description:The key risk factor for glaucoma is elevation of intraocular pressure (IOP) and alleviating it is the only effective therapeutic approach to inhibit further vision loss. IOP is regulated by the flow of aqueous humour across resistive tissues, and a reduction in outflow facility, is responsible for the IOP elevation in glaucoma. Measurement of outflow facility is therefore important when investigating the pathophysiology of glaucoma and testing candidate treatments for lowering IOP. Due to similar anatomy and response to pharmacological treatments, mouse eyes are a common model of human aqueous humour dynamics. The ex vivo preparation, in which an enucleated mouse eye is mounted in a temperature controlled bath and cannulated, has been well characterised and is widely used. The postmortem in situ model, in which the eyes are perfused within the cadaver, has received relatively little attention. In this study, we investigate the postmortem in situ model using the iPerfusion system, with a particular focus on i) the presence or absence of pressure-independent flow, ii) the effect of evaporation on measured flow rates and iii) the magnitude and pressure dependence of outflow facility and how these properties are affected by postmortem changes. Measurements immediately after cannulation and following multi-pressure facility measurement demonstrated negligible pressure-independent flow in postmortem eyes, in contrast to assumptions made in previous studies. Using a humidity chamber, we investigated whether the humidity of the surrounding air would influence measured flow rates. We found that at room levels of humidity, evaporation of saline droplets on the eye resulted in artefactual flow rates with a magnitude comparable to outflow, which were eliminated by a high relative humidity (>85%) environment. Average postmortem outflow facility was ∼4 nl/min/mmHg, similar to values observed ex vivo, irrespective of whether a postmortem delay was introduced prior to cannulation. The intra-animal variability of measured outflow facility values was also reduced relative to previous ex vivo data. The pressure-dependence of outflow facility was reduced in the postmortem relative to ex vivo model, and practically eliminated when eyes were cannulated >40 min after euthanisation. Overall, our results indicate that the moderately increased technical complexity associated with postmortem perfusion provides reduced variability and reduced pressure-dependence in outflow facility, when experimental conditions are properly controlled.
Project description: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 <0.1 mmHg resolution and settling times less than 2 seconds. In vitro tests were carried out to characterize system performance. Then, as a proof of concept, we used the system to manipulate IOP in tree shrews (Tupaia belangeri) while video of the retinal vessels was recorded and the caliber of a selected vein was quantified. Modulating IOP using our system elicited a rapid change in the appearance of the retinal vein of interest: IOP was lowered from 10 to 3 mmHg, and retinal vein caliber sharply increased as IOP decreased from 7 to 5 mmHg. Another important feature of this technology is its capability to measure ocular compliance and outflow facility in vivo, as demonstrated in tree shrews. Collectively, these proof-of-concept demonstrations support the utility of this system to manipulate IOP for a variety of useful applications in ocular biomechanics, and provide a framework for further study of the mechanisms of retinal venous pulsation.
Project description:An increasing number of studies indicate that the optic nerve head of the eye is sensitive not only to changes in intraocular pressure (IOP), but also to intracranial pressure (ICP). This study examines changes to optic nerve and retinal structure in a rat model in response to a range of IOP and ICP levels using optical coherence tomography. Furthermore, we examine the functional sequelae of these structural changes by quantifying the effect of pressure changes on the electroretinogram. IOP elevation (10-90 mmHg) induces progressive deformation of the optic nerve head and retinal surface (P < 0.05), compression of the retina (P < 0.05) and bipolar cell (b-wave), and retinal ganglion cell (scotopic threshold response) dysfunction (P < 0.05). Simultaneously altering ICP (-5 to 30 mmHg) modifies these IOP-induced responses, with lower ICP (-5 mmHg) exacerbating and higher ICP (15-30 mmHg) ameliorating structural and functional deficits. Thus, the balance between IOP and ICP (optic nerve pressure gradient, ONPG = IOP - ICP) plays an important role in optic nerve integrity. Structural and functional parameters exhibit a two-phase relationship to ONPG, with structural changes being more sensitive to ONPG modification (threshold = -0.6 to 11.3 mmHg) compared with functional changes (threshold = 49.7-54.6 mmHg). These findings have implications for diseases including glaucoma, intracranial hypertension, and long-term exposure to microgravity.
Project description:Elevated intraocular pressure (IOP) is the predominant risk factor for glaucoma, and reducing IOP is the only successful strategy to prevent further glaucomatous vision loss. IOP is determined by the balance between the rates of aqueous humour secretion and outflow, and a pathological reduction in the hydraulic conductance of outflow, known as outflow facility, is responsible for IOP elevation in glaucoma. Mouse models are often used to investigate the mechanisms controlling outflow facility, but the diminutive size of the mouse eye makes measurement of outflow technically challenging. In this study, we present a new approach to measure and analyse outflow facility using iPerfusion™, which incorporates an actuated pressure reservoir, thermal flow sensor, differential pressure measurement and an automated computerised interface. In enucleated eyes from C57BL/6J mice, the flow-pressure relationship is highly non-linear and is well represented by an empirical power law model that describes the pressure dependence of outflow facility. At zero pressure, the measured flow is indistinguishable from zero, confirming the absence of any significant pressure independent flow in enucleated eyes. Comparison with the commonly used 2-parameter linear outflow model reveals that inappropriate application of a linear fit to a non-linear flow-pressure relationship introduces considerable errors in the estimation of outflow facility and leads to the false impression of pressure-independent outflow. Data from a population of enucleated eyes from C57BL/6J mice show that outflow facility is best described by a lognormal distribution, with 6-fold variability between individuals, but with relatively tight correlation of facility between fellow eyes. iPerfusion represents a platform technology to accurately and robustly characterise the flow-pressure relationship in enucleated mouse eyes for the purpose of glaucoma research and with minor modifications, may be applied in vivo to mice, as well as to eyes from other species or different biofluidic systems.
Project description: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.
Project description:PURPOSE:To investigate whether microsurgical excision of trabecular meshwork (TM) in an ex vivo pigmentary glaucoma model can normalize the hypertensive phenotype. METHODS:Eight eyes of a porcine pigmentary glaucoma model underwent 90° of microsurgical TM excision with an aspirating dual-blade (Goniotome (G)). 24 hours later, additional 90° of TM were removed. Anterior segments with sham surgeries served as the control (C). Outflow facility and intraocular pressure (IOP) were analyzed. Histology with hematoxylin and eosin (H&E) was obtained. RESULTS:After the first 90° TM excision, IOP was significantly lower in G (10.2±2.4 mmHg, n = 7) than C (20.0±2.0mmHg, n = 8, P<0.01). Outflow facility in G (0.38±0.07 ?l/min/mmHg) was higher than C (0.16±0.02 ?l/min/mmHg, P<0.01). After the second 90° TM excision, IOP in G (6.46±0.81 mmHg, n = 7) was significantly lower than C (20.3±1.7 mmHg, n = 8, P<0.001), while the outflow facility in G (0.50±0.05 ?l/min/mmHg, n = 7) was higher than C (0.16±0.01 ?l/min/mmHg, n = 8, P<0.001). Compared to the first excision, excision of an additional 90° did not change of IOP (P = 0.20) or outflow facility (P = 0.17) further. CONCLUSIONS:Excision of 90° of TM in a pigmentary glaucoma model using an aspirating dual-blade decreased IOP and increased outflow facility.
Project description:<h4>Purpose</h4>The effective management of glaucoma is hindered by an incomplete understanding of its pathologic mechanism. While important, intraocular pressure (IOP) alone is inadequate in explaining glaucoma. Non-IOP-mediated risk factors such as cerebrospinal fluid (CSF) pressure have been reported to contribute to glaucomatous optic neuropathy. Due to the difficulty associated with experimental measurement of the salient variables, such as the retrobulbar CSF pressure, porosity of the subarachnoid space (SAS), and especially those concerned with the perioptic SAS, there remains a limited understanding of the CSF behavior contributing to the translaminar pressure gradient (TLPG), hypothesized to be a critical factor in the development of glaucoma.<h4>Method</h4>An integrated compartmental model describing the intracranial and orbital CSF dynamics, coupled with intraocular dynamics, is developed based on first principles of fluid mechanics. A sensitivity analysis is performed to identify anatomic characteristics that significantly affect the retrobulbar subarachnoid space (RSAS) pressure and, consequently, the TLPG.<h4>Results</h4>Of the 28 parameters considered, the RSAS pressure is most sensitive to CSF flow resistance in the optic nerve SAS and the potential lymphatic outflow from the optic nerve SAS into the orbital space. A parametric study demonstrates that a combination of resistance in the range of 1.600 × 1012 - 1.930 × 1012 Pa s/m3 (200.0 - 241.3 mm Hg min/mL) with 5% to 10% lymphatic CSF outflow yields RSAS pressures that are consistent with the limited number of studies in the literature.<h4>Conclusions</h4>The results suggest that a small percentage of lymphatic CSF outflow through the optic nerve SAS is likely. In addition, flow resistance in the orbital CSF space, hypothesized to be a function of patient-specific optic nerve SAS architecture and optic canal geometry, is a critical parameter in regulating the RSAS pressure and TLPG.
Project description:The spaceflight-associated neuro-ocular syndrome (SANS), which may present after prolonged exposure to microgravity, is thought to occur due to elevated intracranial pressure (ICP). Intracranial pressure interacts with intraocular pressure (IOP) to define the translaminar pressure difference (TLPD; IOP-ICP). We combined inducible models of ICP and IOP elevation in mice to interrogate the relationships among ICP, IOP, and TLPD, and to determine if IOP elevation could mitigate the phenotypes typically caused by elevated ICP and thereby serve as a countermeasure for SANS. Ten C57BL6J mice of both genders underwent experimental elevation of ICP via infusion of artificial cerebrospinal fluid into the subarachnoid space. One eye also underwent experimental elevation of IOP using the bead injection model. Intraocular pressure and ICP were monitored for 2 weeks. Optokinetic-based contrast sensitivity was measured at baseline and after 2 weeks, and post-mortem studies of optic nerve and retina anatomy were performed. Photopic contrast sensitivity was reduced more in IOP elevated than control eyes. Scotopic contrast sensitivity was reduced similarly in IOP elevated and control eyes. However, the pattern of scotopic vision loss was not uniform in IOP elevated eyes; there was minimal loss in eyes that most closely approximated the normal TLPD. Optic nerve axon loss, increased optic nerve disorganization, and retinal ganglion cell loss all occurred similarly between IOP elevated and control eyes. Elevation of IOP in eyes with elevated ICP may counterbalance some effects on vision loss but exacerbate others, suggesting complex relationships among IOP, ICP, and TLPD.
Project description:PURPOSE:Netarsudil, an inhibitor of Rho kinase and a norepinephrine transporter, has been shown to lower elevated intraocular pressure (IOP) in controlled studies of patients with open-angle glaucoma and ocular hypertension, and in healthy volunteers. The mechanism of this ocular hypotensive effect in humans is unknown. METHODS:The objective of this study was to evaluate the effect of netarsudil 0.02% on aqueous humor dynamics (AHD) parameters. In this double-masked, vehicle-controlled, paired-eye comparison study, 11 healthy volunteers received topical netarsudil ophthalmic solution 0.02% or its vehicle once daily for 7 days (morning dosing). The primary endpoints were the change in AHD parameters, compared between active and vehicle-treated eyes. RESULTS:In netarsudil-treated eyes, diurnal outflow facility increased from 0.27?±?0.10??L/min/mmHg to 0.33?±?0.11??L/min/mmHg (+22%; P?=?0.02) after 7 days of treatment. In placebo-treated eyes, diurnal outflow facility did not significantly change (P?=?0.94). The difference between netarsudil and placebo eyes in diurnal change of outflow facility was 0.08??L/min/mmHg (P?<?0.001). Diurnal episcleral venous pressure (EVP) in netarsudil-treated eyes decreased from 7.9?±?1.2?mmHg to 7.2?±?1.8 (-10%; P?=?0.01). Diurnal EVP was not significantly different between netarsudil- and placebo-treated eyes. There was a trend toward decreasing aqueous humor flow rate (-15%; P?=?0.08). No treatment changes were seen in uveoscleral outflow rate. CONCLUSIONS:Once-daily dosing of netarsudil ophthalmic solution 0.02% lowered IOP through increasing trabecular outflow facility and reducing EVP. This suggests a combination of mechanisms that affect both the proximal and distal outflow pathways.
Project description:Purpose:To characterize the relative contributions of intraocular pressure (IOP) and intracranial pressure (ICP) on lamina cribrosa (LC) behavior, specifically LC depth (LCD) and LC peak strain. Methods:An axially symmetric finite element model of the posterior eye was constructed with an elongated optic nerve and retro-orbital subarachnoid space ensheathed by pia and dura mater. The mechanical environment in LC was evaluated with ICP ranging from 5 to 15 mmHg and IOP from 10 to 45 mmHg. LCD and LC peak strains at various ICP and IOP levels were estimated using full factorial experiments. Multiple linear regression analyses were then applied to estimate LCD and LC peak strain using ICP and IOP as independent variables. Results:Both increased ICP and decreased IOP led to a smaller LCD and LC peak strain. The regression correlation coefficient for LCD was -1.047 for ICP and 1.049 for IOP, and the ratio of the two regression coefficients was -1.0. The regression correlation coefficient for LC peak strain was -0.025 for ICP and 0.106 for IOP, and the ratio of the two regression coefficients was -0.24. A stiffer sclera increased LCD but decreased LC peak strain; besides, it increased the relative contribution of ICP on the LCD but decreased that on the LC peak strain. Conclusions:ICP and IOP have opposing effects on LCD and LC peak strain. While their effects on LCD are equivalent, the effect of IOP on LC peak strain is 3 times larger than that of ICP. The influences of these pressure are dependent on sclera material properties, which might explain the pathogenesis of ocular hypertension and normal-tension glaucoma.