There is not a clinically available technique for measuring the physiological traits causing obstructive sleep apnea (OSA). Therefore, it is often difficult to determine why an individual has OSA or to what extent the various traits contribute to the development of OSA. In this study, we present a noninvasive method for measuring four important physiological traits causing OSA: 1) pharyngeal anatomy/collapsibility, 2) ventilatory control system gain (loop gain), 3) the ability of the upper airway to dilate/stiffen in response to an increase in ventilatory drive, and 4) arousal threshold. These variables are measured using a single maneuver in which continuous positive airway pressure (CPAP) is dropped from an optimum to various suboptimum pressures for 3- to 5-min intervals during sleep. Each individual's set of traits is entered into a physiological model of OSA that graphically illustrates the relative importance of each trait in that individual. Results from 14 subjects (10 with OSA) are described. Repeatability measurements from separate nights are also presented for four subjects. The measurements and model illustrate the multifactorial nature of OSA pathogenesis and how, in some individuals, small adjustments of one or another trait (which might be achievable with non-CPAP agents) could potentially treat OSA. This technique could conceivably be used clinically to define a patient's physiology and guide therapy based on the traits.

A, White DP. A simplified method for determining phenotypic traits in patients with obstructive sleep apnea. J Appl Physiol 114: 911-922, 2013. First published January 24, 2013 doi:10.1152/japplphysiol.00747.2012.-We previously published a method for measuring several physiological traits causing obstructive sleep apnea (OSA). The method, however, had a relatively low success rate (76%) and required mathematical modeling, potentially limiting its application. This paper presents a substantial revision of that technique. To make the measurements, continuous positive airway pressure (CPAP) was manipulated during sleep to quantify 1) eupneic ventilatory demand, 2) the level of ventilation at which arousals begin to occur, 3) ventilation off CPAP (nasal pressure ϭ 0 cmH 2O) when the pharyngeal muscles are activated during sleep, and 4) ventilation off CPAP when the pharyngeal muscles are relatively passive. These traits could be determined in all 13 participants (100% success rate). There was substantial intersubject variability in the reduction in ventilation that individuals could tolerate before having arousals (difference between ventilations #1 and #2 ranged from 0.7 to 2.9 liters/min) and in the amount of ventilatory compensation that individuals could generate (difference between ventilations #3 and #4 ranged from Ϫ0.5 to 5.5 liters/min). Importantly, the measurements accurately reflected clinical metrics; the difference between ventilations #2 and #3, a measure of the gap that must be overcome to achieve stable breathing during sleep, correlated with the apneahypopnea index (r ϭ 0.9, P Ͻ 0.001). An additional procedure was added to the technique to measure loop gain (sensitivity of the ventilatory control system), which allowed arousal threshold and upper airway gain (response of the upper airway to increasing ventilatory drive) to be quantified as well. Of note, the traits were generally repeatable when measured on a second night in 5 individuals. This technique is a relatively simple way of defining mechanisms underlying OSA and could potentially be used in a clinical setting to individualize therapy. pathophysiology of sleep apnea; loop gain; pharyngeal critical closing pressure; upper airway; arousal threshold RECENT EVIDENCE SUGGESTS that obstructive sleep apnea (OSA) is a multifactorial disorder. Contributing factors include a small or collapsible pharyngeal airway (9, 12, 23), a high loop gain (large ventilatory response to a ventilatory disturbance) (2,11,21,25,26,31), poor pharyngeal muscle responsiveness during sleep (5, 14 -16, 20, 27, 29), and a low respiratory arousal threshold (13, 28). The relative contribution of these traits varies substantially between individuals (24, 30).Despite the multifactorial nature of OSA, common therapies [continuous positive airway pressure (CPAP), upper airway surgery, dental appliances] are directed at only one trait: the abnormal airway anatomy. Moreover, the most effective treatment, CPAP, has an acceptance rate of only ϳ50% (8, 17). We believe that if the tr...

Visual stimulation outside the classical receptive field can have pronounced effects on cat retinal ganglion cells. We characterized the effects of such stimulation by varying the contrast, spatial frequency, temporal frequency, and spatial extent of remote drifting sinusoidal gratings. We found that the mean firing rate of some X-cells and most Y-cells increased to remote gratings of low spatial frequency and high temporal frequency and decreased to ones of high spatial frequency and low temporal frequency. At least 10-20% contrast was required to see either effect, which quickly saturated at higher contrasts. Both effects were substantial, raising or lowering the mean rate of some cells by over 40 impulses/sec. Classical receptive field mechanisms were not involved because the remote gratings caused little or no response modulation. We conclude that, in addition to a mean-increasing mechanism known from previous work, a mean-decreasing one operates in the cat retina. This mechanism prefers slower motion and resolves finer patterns than the mean-increasing one. We incorporate these findings into a model consisting of pools of small and large rectifying subunits of opposite polarity. Model estimates of subunit radius were primarily independent of eccentricity and averaged ϳ0.15 and ϳ0.60°for the mean-decreasing and mean-increasing mechanisms, respectively. This makes the subunits approximately the center size of central X-and Y-cells. Because smooth movements of the eyes, head, or body should engage these mechanisms under natural conditions, we propose that the mean rate changes that would ensue are functionally relevant to cat vision.

To assess the information encoded in retinal spike trains and how it might be decoded by recipient neurons in the brain, we recorded from individual cat X and Y ganglion cells and visually stimulated them with randomly modulated patterns of various contrast and spatial configuration. For each pattern, we estimated the information rate of the cells using linear or nonlinear algorithms and for some patterns by directly measuring response probability distributions. We show that ganglion cell spike trains contain information from the receptive field center and surround, that the center and surround have similar signaling capacity, that antagonism between the mechanisms reduces information transmission, and that the total information rate is limited. We also show that a linear decoding algorithm can capture all of the information available in retinal spike trains about weak inputs, but it misses a substantial amount about strong inputs. For the strongest stimulus we used, the information rate of the best linear decoder averaged 40-70 bits/s across ganglion cell types, while the directly measured rate was around 20-40 bits/s greater. This implies that under certain stimulus conditions, visual information is encoded in the temporal structure of retinal spike trains and that a nonlinear decoding algorithm is needed to extract the temporally coded information. Using simulated spike trains, we demonstrate that much of the temporal structure may be explained by the threshold for spike generation and is not necessarily indicative of a complex coding scheme.

Ocular diseases can deteriorate vision to the point of blindness and thus can have a major impact on the daily life of an individual. Conventional therapies are unable to provide absolute therapy for all ocular diseases due to the several limitations during drug delivery across the blood-retinal barrier, making it a major clinical challenge. With recent developments, the vast number of publications undergird the need for nanotechnology-based drug delivery systems in treating ocular diseases. The tool of nanotechnology provides several essential advantages, including sustained drug release and specific tissue targeting. Additionally, comprehensive in vitro and in vivo studies have suggested a better uptake of nanoparticles across ocular barriers. Nanoparticles can overcome the blood-retinal barrier and consequently increase ocular penetration and improve the bioavailability of the drug. In this review, we aim to summarize the development of organic and inorganic nanoparticles for ophthalmic applications. We highlight the potential nanoformulations in clinical trials as well as the products that have become a commercial reality.