The Parasympathetic Nervous System and DED

The parasympathetic nervous system (PNS), involved in the “rest and digest” response, and the sympathetic nervous system, involved in the “fight or flight” response, are the two main divisions of the autonomic nervous system. The PNS operates in the craniosacral and sacral segments of the central nervous system, and involves the oculomotor (III), facial (VII), glossopharyngeal (IX), and vagus (X) nerves. The primary neurotransmitters used by these nerves, acetylcholine (ACh) and vasoactive intestinal peptide (VIP), work together to promote the “rest and digest” functions of the body (eg, constricting pupils, slowing heart rate, and maintaining gut motility for digestion).¹

The motor branch of the seventh nerve serves as part of the postganglionic parasympathetic pathway that innervates the lacrimal functional unit for tear production, distribution, and clearance. The lacrimal gland has mainly muscarinic ACh receptors, and the primary neurotransmitter responsible is ACh. Therefore, if we want to stimulate tear production in conditions such as aqueous-deficient dry eye disease (DED), we should focus on targeting the lacrimal gland tissue, nerve, receptor, and/or neurotransmitter.²

HOW ARE THE PNS AND DED CONNECTED?

Because the PNS is mainly responsible for tear production in the lacrimal gland, when the superficial petrosal nerve is denervated, tear production is reduced by 70%. Conversely, when we stimulate the PNS, we can increase tear production.²

Additionally, the PNS plays a role in immune modulation, with the cholinergic antiinflammatory pathway linking the autonomic nervous system and the immune system, primarily through the parasympathetic nerves, especially the vagus nerve, along with ACh and its receptors. This pathway can activate and regulate immune cell functions, contributing to its antiinflammatory role and affecting the development of various autoimmune diseases.³ Anticholinergic medications, such as antihistamines and antidepressants, also downregulate the binding of ACh to its muscarinic receptor in the lacrimal gland, leading to overall reduced tear production.²

In conditions such as Sjögren syndrome, inflammation further reduces ACh release and tear production. Furthermore, the presence of muscarinic receptor antibodies that block ACh binding to the receptors may also lead to decreased tear production.⁴ It has been suggested that serum autoantibodies against muscarinic ACh may even serve as an early marker for Sjögren syndrome.⁵ Because serum ACh cannot be measured successfully, clinicians must use signs and symptoms to help guide treatment for these patients.

It is worth mentioning that studies have confirmed the presence of VIP receptors in human meibomian gland acini that may be indicated in cell proliferation, and that exogenous application of VIP can stimulate goblet cell secretion; however, further data are needed to confirm the exact role of VIP in DED.⁶ Overall, the role of the PNS in aqueous-deficient dry eye is well established (its role in evaporative dry eye and the meibomian glands is less so).

IS THE VAGUS NERVE INDICATED IN DED?

Animal studies have indicated that the vagal cholinergic pathway has antiinflammatory properties and is able to regulate peripheral inflammation in our vital organs.⁷ Although the vagus nerve does not directly innervate the eye (Figure), its connection to the parasympathetic pathways is ACh. One study postulated that by supplementing this vital neurotransmitter, we may affect tear production and treat systemic inflammation associated with DED.⁸ To further support cholinergic neurostimulation as a treatment for chronic inflammation, another study recently showed that chronic fatigue can be improved by stimulating the vagus nerve in patients affected by Sjögren syndrome.⁹

Vagus nerve stimulation reduces inflammation by decreasing neutrophil recruitment, macrophage migration, and cytokine release. Noninvasive cervical vagus nerve stimulation can alleviate arthritis severity and suppress proinflammatory cytokines in both patients with RA and animal models. Similarly, invasive vagus nerve stimulation with implantable electrodes reduces tumor necrosis factor release in the blood of patients with RA. This suggests that short-term electrical stimulation of the vagus nerve could be a promising and cost-effective treatment for controlling inflammation and may be helpful in immune-mediated dry eye management.

Systemic control of inflammation and related DED may involve supplementing the vagus and lacrimal nerves with ACh neurotransmitters. The effects of Parasym Plus Eyes (TJ Nutrition), an OTC ACh supplement of proprietary composition, are being studied to highlight the role of PNS activation in DED.

DRY EYE TREATMENT OPTIONS INVOLVING THE PNS

There are two approved treatments for DED that involve activation of the PNS pharmacologically and mechanically.

Through neurostimulation, we can target the nicotinic ACh receptor via the anterior ethmoidal nerve to agonistically bind ACh, which eventually communicates with the parasympathetic nervous system to stimulate tear production directly and aims to restore tear homeostasis. Nasally administered varenicline 0.03 mg (Tyrvaya, Viatris) has been shown to increase Schirmer scores and Ocular Surface Disease Index scores after 4 weeks of treatment compared with the vehicle, resulting in a clinically meaningful treatment option for patients with DED.¹⁰

Additionally, mechanical stimulation of the anterior ethmoidal nerve activates binding of ACh to its muscarinic receptors along the trigeminal afferent pathway. The commercially available iTear 100 (Olympic Ophthalmics) has improved Schirmer scores in 94% of patients after 30 days of use.¹¹

CAN BEHAVIORAL MODIFICATIONS ACTIVATE THE PNS?

One study attempted to elucidate the connection between DED and autonomic nervous system regulation. The researchers found that more severe symptoms and lower tear breakup time were associated with large fluctuations in autonomic nervous system regulation, suggesting a connection between DED and stress.¹² Further studies are necessary to understand the mechanism of tear breakup time and meibomian gland output.

Sufficient evidence suggests that getting enough sleep is crucial in regulating the PNS. Sleeping less than 6 hours, experiencing sleep deprivation, having poor sleep quality, and experiencing sleep disorders are all linked to symptoms of DED.^13-16 Extended periods of time spent staring at digital devices increases blue light exposure and has been shown to decrease blink rate. This heightened exposure to blue light can disrupt the circadian rhythm, potentially affecting sleep quality and further contributing to symptoms of DED.

Autonomic thermoregulation is a higher-order process by which the autonomic nervous system regulates appropriate heat throughout the body to maintain homeostasis. It is known that heat application assists in the treatment of evaporative DED, but the connection between PNS regulation, thermoregulation, and evaporative DED is still not understood. Umay Rest (Umay) provides heat application over the eyelids, simultaneously delivering thermoregulation, better sleep quality, and meibomian gland treatment. When assessing the effect of the Umay Rest device on 500 participants, it was found that it resulted in statistically significant enhancements in participants’ sleep quality (67%), reduction in stress/anxiety levels (65%), and alleviation of visual/ocular symptoms associated with screen use (74%).¹⁷

Deep breathing is also known to regulate the PNS. Interestingly, when healthy women engaged in deep breathing for 3 minutes, their tear secretion improved 15 minutes after, indicating that the PNS is involved in tear production, as activated by deep abdominal breathing.¹⁸ Other behavioral modifications known to regulate the PNS that therefore may be indicated in DED management include meditation, mindfulness, gratitude journaling, yoga, chanting, laughing, and music therapy.

FUTURE DEVELOPMENTS

As knowledge of the autonomic nervous system and its role in DED advances, it is evident that DED is more than simply a disease of the eye.