Report of the Neurobiology Subcommittee Members: Fiona Stapleton (Co-Chair & SC Liason)

1. Report of the Neurobiology Subcommittee Members: Fiona Stapleton (Co-Chair & SC Liason) Carl Marfurt Blanka Golebiowski Mark Rosenblatt (Co-Chair) David Bereiter Carolyn Begley Darlene Dartt Juana Gallar Carlos Belmonte Pedram Hamrah Mark Willcox (Harmonization Subcommittee)

2. Neurobiology Subcommittee Scope: • Anatomy and morphological characteristics • Molecular and cellular neurobiology of ocular discomfort and pain. • Limited data on neurobiology of CL wear, evidence generated for dry eye disease was examined. • Inflammatory pathway, impact of hyperosmolarity, peripheral and central mediators of ocular sensation. • Stimulus delivered by CL & how this might impact those peripheral and central processes • Neurobiological view of potential treatments. • Areas of future research identified.

3. Neurobiology Subcommittee Sensory nerves: • Area of the ocular surface which interacts with the CL • Anatomy, morphology and neurochemistry • Corneal innervation is well characterised; limited information on conjunctiva & eyelid margin1,2 • Human corneal sensory neuropeptides predominantly CGRP & substance P3 • No evidence yet that CLD impacts morphology or neurochemistry

4. Neurobiology Subcommittee Neurophysiology & sensation - PNS: • Functional types of ocular sensory neurons4 • Polymodalnociceptors (70%) • Mechano-nociceptors (15-20%) • Cold-sensitive receptors (10-15%) • Sensitisation of polymodal & cold nociceptors • Transduction /coding of stimuli modulated by many ion channels5 • Transient Receptor Protein (TRP) Channels – polymodal activation • Others ; Acid Sensing Ion Channels (ASICs) and K+ channels

5. Neurobiology Subcommittee Neurophysiology & sensation - PNS: • Relationship with sensation? • Ion channels not functionally associated with nociceptor type5 • Stimulus is encoded based on combination of different ion channels in each neuronal type • Abnormal peripheral signalling may occur with persistent stimulation or inflammation - conceivable in CLD. • Evidence in CLD limited. Increased conjunctival mechanical sensitivity in symptomatic CL wear6; altered response to suprathreshold stimuli7

6. Neurobiology Subcommittee Neurophysiology & sensation: CNS: • Complex nature of perceptions suggests integration at higher brain centres

7. Neurobiology Subcommittee Summary of the neurophysiology of CLD

8. Neurobiology Subcommittee Treatments (neurobiological targets): • Reduce mechanical stimulation • Alter materials, change friction modulus8,9 • Reduce mechanical insult to the conjunctiva9 • Chemical • Reduce activation/sensitization of polymodal nociceptors10 • Control pH & osmolarity known to activate receptors11 • Limit dehydration12 • Pharmacological agents • Neuropathic pain, altered excitability of corneal nerves13 • Others, e.g. NGF to treat nerve architecture or αNGF manage symptomatology14

9. Neurobiology Subcommittee Future directions for research: • Pain/discomfort questionnaires • Morphological and functional studies • Animal Models • Contact lens wear • Pain models • Natural history or chronicity of discomfort

10. Neurobiology Subcommittee Summary: • Corneal nerves only well studied • Current understanding of ocular surface sensation is incomplete • Relevant aspects of CL wear in CLD: • physical interaction with ocular surface • hyperosmolarity • chemical mediators in MPS/packaging solutions • inflammatory mediators • Sensory changes due to neural adaptation to a continuous stimulus or neural sensitization in response to hyperosmolarity or inflammatory mediators

11. Neurobiology Subcommittee Summary: • Future directed treatments • Lens related factors • Agents to modulate peripheral & central nervous system responses • Development of sensitive measurement & analytical techniques at all stages of discomfort pathway.

12. Thank you! QUESTIONS?

13. Neurobiology Subcommittee Key References: • Al-Aqaba MA, Fares U, Suleman H, Lowe J, Dua HS. Architecture and distribution of human corneal nerves. Br J Ophthalmol 2010;94:784-789. • Bron AJ, Tripathi, R., and Tripathi, B. Wolff's Anatomy of the Eye and Orbit. 8th ed. London: Chapman and Hall Medical; 1997. • Marfurt CF. Peptidergic innervation of the cornea: anatomical and functional consideration. In: Troger JaK, G. (ed), Neuropeptides in the Eye. Kerala: Research Signpost; 2009:23-37. • Belmonte C, Aracil A, Acosta MC, Luna C, Gallar J. Nerves and sensations from the eye surface. Ocul Surf 2004;2:248-253. • Viana F, Belmonte C. Transduction and encoding of noxious stimulus. In: Schmidt RF, Gebhart GF (eds), Encyclopedia of Pain: Springer; 2013. • Tan et al., IOVS 1997; 38 ARVO abstract S1336 • Chen J, Simpson TL. A role of corneal mechanical adaptation in contact lens-related dry eye symptoms. Invest Ophthalmol Vis Sci 2011;52:1200-1205. • Holden BA, Stephenson A, Stretton S, et al. Superior epithelial arcuate lesions with soft contact lens wear. Optom Vis Sci 2001;78:9-12.

14. Neurobiology Subcommittee Key References: • Santodomingo-Rubido J, Wolffsohn J, Gilmartin B. Conjunctival epithelial flaps with 18 months of silicone hydrogel contact lens wear. Eye Contact Lens 2008;34:35-38. • Lazon de la Jara P, Papas E, Diec J et al. Effect of lens care systems on the clinical performance of a contact lens. Optom Vis Sci 2013;90:344-350. • Stahl U, Willcox M, Stapleton F. Role of hypo-osmotic saline drops in ocular comfort during contact lens wear. Contact Lens Ant Eye 2010;33:68-75. • Peterson RC, Wolffson JS, Nick J et al. Clinical performance of daily disposable soft contact lenses using sustained release technology. Contact Lens Ant Eye 2006;29:137-134. • Lichtinger A, Purcell TL, Schanzlin DJ, Chayet AS. Gabapentin for postoperative pain after photorefractive keratectomy: a prospective, randomized, double-blind, placebo-controlled trial. J Refract Surg 2011;27:613-617. • Eibl JK, Strasser BC, Ross GM. Structural, biological, and pharmacological strategies for the inhibition of nerve growth factor. Neurochem Int 2012;61:1266-1275.