Early phase of pupil dilation is mediated by the peripheral parasympathetic pathway.

Pupil diameter fluctuates in association with changes in brain states induced by the neuromodulator systems. However, it remains unclear how the neuromodulator systems control the activity of the iris sphincter (constrictor) and dilator muscles to change the pupil size. The present study compared temporal patterns of pupil dilation during movement when each muscle was pharmacologically manipulated in the human eye. When the iris sphincter muscle was blocked with tropicamide, the latency of pupil dilation was delayed and the magnitude of pupil dilation was reduced during movement. In contrast, when the iris dilator muscle was continuously stimulated with phenylephrine, the latency and magnitude of rapid pupil dilation did not differ from the untreated control eye, but sustained pupil dilation was reduced until the end of movement. These results suggest that the iris sphincter muscle, which is under the control of the parasympathetic pathway, is quickly modulated by the neuromodulator system and plays a major role in rapid pupil dilation. However, the iris dilator muscle receives signals from the neuromodulator system with a slow latency and is involved in maintaining sustained pupil dilation.NEW & NOTEWORTHY By pharmacologically manipulating the pupil dilator and constrictor muscles of human eye separately, we found that the pupil constrictor muscle is a primary controller of rapid pupil dilation upon brain arousal. However, the pupil dilator muscle, which is innervated by the sympathetic nervous system and is generally considered as a major regulator of pupil dilation, is not involved in rapid pupil dilation, but was involved in long-lasting pupil dilation.

Desipramine Increases Genioglossus Activity and Reduces Upper Airway Collapsibility during Non-REM Sleep in Healthy Subjects.

RATIONALE: Obstructive sleep apnea is a state-dependent disease. One of the key factors that triggers upper airway collapse is decreased pharyngeal dilator muscle activity during sleep. To date, there have not been effective methods to reverse pharyngeal hypotonia pharmacologically in sleeping humans. OBJECTIVES: We tested the hypothesis that administration of desipramine 200 mg prevents the state-related reduction in genioglossus activity that occurs during sleep and thereby decreases pharyngeal collapsibility. METHODS: We conducted a placebo-controlled, double-blind, crossover trial with 10 healthy participants. Participants received active treatment or placebo in randomized order 2 hours before sleep in the physiology laboratory. MEASUREMENTS AND MAIN RESULTS: Genioglossus activity during wakefulness and sleep, genioglossus muscle responsiveness to negative epiglottic pressure, and upper airway collapsibility during passive and active conditions were compared between on- and off-drug states. Desipramine abolished the normal reduction of genioglossus activity from wakefulness to non-REM sleep that occurred on the placebo night. Specifically, tonic (median, 96% [86-120] vs. 75% [50-92] wakefulness; P = 0.01) but not phasic genioglossus activity was higher with desipramine compared with placebo. Upper airway collapsibility was also reduced with desipramine compared with placebo (-10.0 cm H2O [-15.2 to -5.8] vs. -8.1 cm H2O [-10.4 to -6.3]; P = 0.037). CONCLUSIONS: Desipramine reduces the state-related drop in tonic genioglossus muscle activity that occurs from wakefulness to non-REM sleep and reduces airway collapsibility. These data provide a rationale for a new pharmacologic therapy for obstructive sleep apnea. Clinical trial registered with www.clinicaltrials.gov (NCT02428478).

Differential neuromotor control of the vertical and longitudinal genioglossus muscle fibers: An overlooked tongue retractor.

INTRODUCTION: The genioglossus (GG) is known to be the main tongue protrusor, and therefore plays a major role in breathing. However, due to the fan shape of the GG fibers, it could be assumed that contraction of the anterior fibers of the GG do not cause tongue protrusion. In this study, we examined the effect of contraction of the anterior-vertical fibers of the GG (GGV) on the tongue and their EMG activity during wakefulness and sleep. The findings were compared to those of the longitudinal fibers (GGL), which, based on their orientation, are responsible for tongue protrusion. METHODS: Fine-wire electrode pairs were placed into the GGV and GGL in 11 patients with untreated OSA. Movement of the tongue during electrical stimulation at each site was videoed. The same electrodes were used to record EMG from both sites during respiratory stimulation by inspiratory loading and CO2 rebreathing during wakefulness. During sleep, repetitive flow limitation events were induced with low-level CPAP to augment GG activity. RESULTS: In all participants, electrical stimulation of GGL and GGV protruded and retracted the tongue, respectively. Respiratory stimulation increased GG activity, but GGV reached only 39 % and 23 % of peak GGL activity during high resistive loading and PCO2 of 65 mmHg, respectively. Flow limitation during sleep increased GGL to levels that were considerably higher than awake baseline, but GGV activity remained tonic or with minimal phasic activity, reaching on average 15 % of GGL peak activity. CONCLUSIONS: Our electrical stimulation findings indicate that GGV is a tongue retractor and depressor. Tongue stimulation for OSA should avoid this area. The EMG results demonstrate that the anterior part of the GG is controlled very differently from the longitudinal protrusive fibers. The GGV responses are similar to those previously found in tongue retractors and peri-pharyngeal muscles other than the GG, in which diminished activation during sleep is likely to be involved in the failure of increasing GGL activity to alleviate flow limitation.

Drive versus Pressure Contributions to Genioglossus Activity in Obstructive Sleep Apnea.

Rationale: Loss of pharyngeal dilator muscle activity is a key determinant of respiratory events in obstructive sleep apnea (OSA). After the withdrawal of wakefulness stimuli to the genioglossus at sleep onset, mechanoreceptor negative pressure and chemoreceptor ventilatory drive feedback govern genioglossus activation during sleep, but the relative contributions of drive and pressure stimuli to genioglossus activity across progressive obstructive events remain unclear. We recently showed that drive typically falls during events, whereas negative pressures increase, providing a means to assess their individual contributions to the time course of genioglossus activity. Objectives: For the first time, we critically test whether the loss of drive could explain the loss of genioglossus activity observed within events in OSA. Methods: We examined the time course of genioglossus activity (EMGgg; intramuscular electromyography), ventilatory drive (intraesophageal diaphragm electromyography), and esophageal pressure during spontaneous respiratory events (using the ensemble-average method) in 42 patients with OSA (apnea-hypopnea index 5-91 events/h). Results: Multivariable regression demonstrated that the falling-then-rising time course of EMGgg may be well explained by falling-then-rising drive and rising negative pressure stimuli (model R = 0.91 [0.88-0.98] [95% confidence interval]). Overall, EMGgg was 2.9-fold (0.47-∞) more closely associated with drive than pressure stimuli (ratio of standardized coefficients, ßdrive:ßpressure; ∞ denotes absent pressure contribution). However, individual patient results were heterogeneous: approximately one-half (n = 22 of 42) exhibited drive-dominant responses (i.e., ßdrive:ßpressure > 2:1), and one-quarter (n = 11 of 42) exhibited pressure-dominant EMGgg responses (i.e., ßdrive:ßpressure < 1:2). Patients exhibiting more drive-dominant EMGgg responses experienced greater event-related EMGgg declines (12.9 [4.8-21.0] %baseline/standard deviation of ßdrive:ßpressure; P = 0.004, adjusted analysis). Conclusions: Loss of genioglossus activity precipitating events in patients with OSA is strongly associated with a contemporaneous loss of drive and is greatest in those whose activity tracks drive rather than pressure stimuli. These findings were upheld for events without prior arousal. Responding to falling drive rather than rising negative pressure during events may be deleterious; future therapeutic strategies whose aim is to sustain genioglossus activity by preferentially enhancing responses to rising pressure rather than falling drive are of interest.

Systemic Administration of Tempol, a Superoxide Dismutase Mimetic, Augments Upper Airway Muscle Activity in Obese Zucker Rats.

Obstructive sleep apnea (OSA) is characterized by repetitive partial/complete collapse of the pharynx during sleep, which results in apnea/hypopnea leading to arterial oxygen desaturations and arousals. Repetitive apnea/hypopnea-arousal episodes cause hypoxia/reoxygenation cycles, which increase free radical generation and oxidative stress that cause motor/sensory nerve impairments and muscle damage. We hypothesize that antioxidants may protect and/or reverse from oxidative stress-induced damage in OSA patients. To understand the acute protective effects of antioxidants on respiratory muscles, we studied the systemic effects of a membrane permeable superoxide dismutase mimetic, Tempol, on genioglossus (EMGGG) and diaphragmatic (EMGDIA) electro-myographic activities, hypoglossal motoneuron (HMN) nerve activity and cardiorespiratory parameters (mean arterial blood pressure, heart rate) in adult isoflurane-anesthetized obese Zucker rats (OZR) and age-matched lean Zucker rats (LZR). Tempol dose-dependently (1-100 mg/kg) increased EMGGG without changing EMGDIA in OZR and LZR. Tempol increased respiratory rate and tidal volume in OZR and LZR. Tempol (1-25 mg/kg) dose-dependently increased HMN nerve activity in healthy Sprague Dawley rats. Tempol (100 mg/kg) increased EMGGG output by 189% in OZR and 163% in LZR. With respect to mechanisms of effect, Tempol (100 mg/kg) did not augment EMGGG after bilateral HMN transection in Sprague Dawley rats. Although future studies are warranted, available data suggest that in addition to its antioxidant and antihypertensive properties, Tempol can selectively augment EMGGG through modulating HMN and this effect may prevent collapsibility and/or improve stability of the upper airway pharyngeal dilator muscles during episodes of partial and/or complete collapse of the upper airway in OSA human subjects.

Congenital Microcoria: Clinical Features and Molecular Genetics.

Iris integrity is required to regulate both the amount of light reaching the retina and intraocular pressure (IOP), with elevated IOP being a major risk factor for glaucoma. Congenital microcoria (MCOR) is an extremely rare, autosomal dominant disease affecting iris development and hindering both of these functions. It is characterized by absent or underdeveloped dilator muscle fibers and immaturity of the iridocorneal angle-where the aqueous humor is drained-which play a central role in IOP regulation. The dilator muscle anomaly is manifested in pinhole pupils (<2 mm) and thin transilluminable irises, causing both hemeralopia and photoaversion. Axial myopia and juvenile open-angle glaucoma are very frequent (80% and 30% of all cases, respectively). It has been suggested that the immaturity of the chamber angle contributes to glaucoma, and myopia has been ascribed to photoaversion and elevated IOP. Though possible, these mechanisms are insufficient. The disease has been tied to chromosome 13q32.1 structural variations. In addition to compromising iris development, modification of the 13q32.1 architecture could alter signaling pathways for axial ocular length and IOP regulation. Here, we summarize the clinical, histological, and molecular features of this disease, and we discuss the possible etiology of associated anomalies.

The Arylabialis Muscle of the Túngara Frog (Engystomops pustulosus).

The current functional model of the anuran larynx includes four pairs of laryngeal muscles. Their contractions do not account, however, for the behavioral control of call complexity observed in male túngara frogs (Engystomops pustulosus), which optionally add a secondary note with distinct harmonic structure to their advertisement call. Examination of the túngara frog's laryngeal morphology through dissection and resin histology has revealed that the m. dilatator laryngis is divided into two separate bundles (superficial and deep). The superficial bundle closely matches the typical description of the m. dilatator laryngis and is well positioned to open the glottis. The deep bundle is exclusively innervated by the short laryngeal nerve and has an attachment to the fibrous mass, an internal laryngeal structure necessary for complex call production. This attachment indicates a separate role for the deep bundle in controlling the complexity of the call. Based on physical separation, exclusive attachments, distinct fiber orientation, exclusive innervation, and potential action, we recognize the deep bundle of the m. dilatator laryngis as a separate muscle. We also revalidate the name m. arylabialis which had been previously used to describe it. The split of the m. dilatator laryngis into two muscles results in a laryngeal innervation pattern that closely matches that of mammals. This study identified a novel laryngeal muscle in túngara frogs, a potential mechanism for the control of call complexity, and revealed new evidence of homologies between the laryngeal structures of amphibians and mammals. Anat Rec, 2019. © 2019 American Association for Anatomy Anat Rec, 303:1966-1976, 2020. © 2019 American Association for Anatomy.

Relationship between the activity of the genioglossus, other peri-pharyngeal muscles and flow mechanics during wakefulness and sleep in patients with OSA and healthy subjects.

INTRODUCTION: In patients with OSA, substantial increases in genioglossus (GG) activity during hypopneas/apneas usually fail to restore normal airflow. The present study was undertaken to evaluate if this phenomenon can be explained by reduced activation of other peri-pharyngeal muscles. METHODS: We recorded EMGs of the GG and four other peri-pharyngeal muscles (accessory dilators, AD), in 8 patients with OSA and 12 healthy subjects, during wakefulness and sleep. Repetitive events of flow limitation were induced during sleep. The events with the highest increases in AD activity were evaluated, to assess if combined activation of both the GG and AD to levels higher than while awake ameliorate airflow reduction during sleep. RESULTS: Flow limitation triggered large increases in GG-EMG, but only modest augmentation in AD activity. Nevertheless, phasic EMG activity was present in 40 % of the ADs during sleep. In multiple events, increases of both GG and AD activity to levels substantially higher than while awake were not associated with improvement in airflow. CONCLUSIONS: We conclude that sleep-induced reduction in AD response to airway obstruction cannot completely explain the failure of upper airway dilators to maintain pharyngeal patency. We speculate that reduction in dilator muscle efficacy may be due to the alterations in motor units recruitment patterns during sleep.

The Tadpole Pupil: Case Series With Review of the Literature and New Considerations.

Tadpole pupil is a rare phenomenon in which segmental spasm of the iris dilator muscle results in a tadpole-shaped pupil. The pupillary distortion is usually unilateral, lasts several minutes, and can recur in clusters. Any segment of the iris can be affected; thus, for some patients, a different-shaped tadpole pupil is noticed from episode to episode. Tadpole pupil most commonly appears spontaneously in young women. Tadpole pupil is not associated with any systemic disorders, but an ipsilateral Horner syndrome is noted in 46% of patients. In this article, we have reviewed the existing literature of tadpole pupil, compiling all the published cases in a table and reporting four additional cases to re-examine the clinical profile of this disorder and to consider the different purported mechanisms as means to understand its possible etiology and treatment. The common denominator in the pathophysiology of tadpole pupil is a focal excessive contraction (segmental spasm) of the iris dilator muscle. Based on various proposed pathophysiologic mechanism of tadpole pupil, we can consider potential forms of treatment.

Morphological alterations within the peripheral fixation of the iris dilator muscle in eyes with pigmentary glaucoma.

PURPOSE: To analyze the peripheral fixation of the iris dilator muscle in normal eyes and in eyes with pigmentary glaucoma (PG). METHODS: Using 63 control eyes (age 18 months-99 years), the peripheral iris dilator was investigated by light microscopy, immunohistochemistry, and electron microscopy. Development was studied using 18 differently aged fetal eyes stained immunohistochemically against α-smooth muscle (SM) actin. The peripheral iris dilator muscle in PG was analyzed using semithin and ultrathin sections of six glutaraldehyde-fixed eyes from three donors aged 38, 62, and 74 years. RESULTS: In normal eyes, the peripheral end of the iris dilator muscle is arranged in a sphincter-like manner. Arcade-shaped tendinous connections associated with myofibroblasts (iridial strands) anchor the iris dilator within the elastic-fibromuscular ciliary meshwork that also serves as fixation area for the elastic tendons of the inner ciliary muscle portions. The iridial strands are innervated and can adapt their length during accommodation. The PG eyes show incomplete circular bundles and iridial strands that are mainly anchored to the iris stroma and the flexible uveal parts of the trabecular meshwork. CONCLUSIONS: The normal anchorage of the peripheral iris dilator and its presumably neuronally regulated length adaptation stabilize the peripheral iris during accommodation. Insufficient fixation in PG could promote posterior bowing of the iris with rubbing against the zonular fibers and pigment liberation from the iris pigmented epithelium.

Effects of Dimethyl Sulfoxide (DMSO) on the Contraction of the Rat Iris Muscle

PURPOSE: To evaluate the effects of DMSO on the iris muscle contractility and to compare DMSO with other detergents(ethanol and triton-x 100). METHODS: After anesthesizing rats with an intraperitoneal injection of pentobarbital sodium, each animal was fixed under microscope. The pupil response to the drugs was examined by CCD camera and the video edge motion detector was used for measurement of alteration of the pupil size. The pupil response to the drugs was recorded by MacLab chart(version 3.6/s). RESULTS: Miosis induced by DMSO was initiated after 5 minutes, peaked at around 30 minutes and maintained until 3 hours after instillation. Miotic effect of DMSO was in a dose dependent manner ranging 0.01%-10% and was not reversed after washout. All detergents used in the present experiment induced miosis, however, DMSO elicited the strongest miotic response. After pretreatment with atropine, DMSO-induced miotic response was not affected, showing similar changes with control group. CONCLUSIONS: Taken together, it is concluded that DMSO induces miosis by inducing relaxation of iris dilator muscle.